JP2022518523A - GPR35 modulator - Google Patents

Abstract

A GPR35 modulator and a method of using these compounds in the treatment of a disease, disorder, or disease are described herein. Pharmaceutical compositions containing such compounds are also described herein. [Selection diagram] None

Description

Mutual Reference This application is a US Provisional Patent Application No. 62 / 769,459 filed on January 24, 2019 and a US Provisional Patent Application No. 62 / 873,703 filed on July 12, 2019. Alleges the benefit of US Provisional Patent Application No. 62 / 928,223 filed October 30, 2019, all of which are incorporated herein by reference in their entirety.

Millions of people have inflammatory or inflammatory diseases. A prominent inflammatory disease is inflammatory bowel disease (IBD). IBD has two common forms, Crohn's disease (CD) and ulcerative colitis (UC), which are chronic and recurrent inflammatory diseases of the gastrointestinal tract. Each of these forms has various side symptoms that are present in the subpopulation of patients with CD and UC. Some CD and UC patients experience a rapid onset of side symptoms, while others experience a relatively late onset.

There are few treatment options available for patients suffering from IBD. Moreover, choosing the appropriate treatment for any individual patient at a given stage of the disease is complicated by the unpredictability of the prognosis of each individual. Current treatment regimens include one or more of anti-inflammatory drug therapies (eg, corticosteroids) and immunomodulatory therapies (eg, anti-TNF treatments). However, nearly half of all patients treated with anti-TNF treatment did not respond to induction of treatment or experienced a loss of response to treatment after a period of time, during which time disease severity progressed significantly. Therefore, there remains a significant need for targeted and effective treatment options that respond to the underlying immunopathogenicity of IBD.

In one aspect, a compound of formula (I ″), or a pharmaceutically acceptable salt or solvate thereof, is provided herein:

式中、
Ｒ^１は、－ＣＨ_２Ｒ^４、－ＣＮ、－Ｂ（ＯＨ）_２、－Ｎ（Ｒ^１０）_２、－ＮＲ^１０Ｃ（Ｏ）Ｒ^９、－Ｃ（Ｏ）ＯＨ、－ＣＨ_２Ｃ（Ｏ）ＯＨ、－Ｃ（Ｏ）Ｎ（Ｒ^１０）_２、－Ｃ（Ｏ）ＮＨＳ（Ｏ）_２Ｎ（Ｒ^１０）_２、－Ｃ_１－６アルキル－ＯＨ、Ｃ_３－８シクロアルキル、

During the ceremony
R ¹ is -CH ₂ R ⁴ , -CN, -B (OH) ₂ , -N (R ¹⁰ ) ₂ , -NR ¹⁰ C (O) R ⁹ , -C (O) OH, -CH ₂ C ( O) OH, -C (O) N (R ¹⁰ ) ₂ , -C (O) NHS (O) ₂ N (R ¹⁰ ) ₂ , -C _1-6 alkyl-OH, C _3-8 cycloalkyl,

、または１つ、２つ、あるいは３つのＲ^８基で随意に置換された５員または６員のヘテロアリールであり；
Ｒ^２は、Ｈ、－ＯＨ、－Ｎ（Ｒ^１０）_２、－ＮＨＳ（Ｏ）_２Ｒ^９、－Ｓ（Ｏ）_２Ｎ（Ｒ^１０）_２、－Ｃ（Ｏ）Ｎ（Ｒ^１０）_２、－ＯＣ（Ｏ）Ｎ（Ｒ^１０）_２、－Ｏ－Ｃ_１－６アルキル、－Ｃ_１－６アルキル－ＯＨ、－Ｃ_１－６アルキル－ＯＲ^９、－Ｃ_１－６アルキル－Ｎ（Ｒ^１０）_２、Ｃ_２－６アルケニル、Ｃ_２－６アルキニル、Ｃ_１－６ハロアルキル、Ｃ_３－８シクロアルキルであり；
Ｒ^３はそれぞれ独立して、ハロゲン、－ＣＮ、－ＯＨ、－ＯＲ^９、－ＳＲ^９、－Ｎ（Ｒ^１０）_２、－ＮＯ_２、－Ｓ（Ｏ）Ｒ^９、－Ｓ（Ｏ）_２Ｒ^９、－ＮＨＳ（Ｏ）_２Ｒ^９、－Ｓ（Ｏ）_２Ｎ（Ｒ^１０）_２、－Ｃ（Ｏ）Ｒ^９、－Ｃ（Ｏ）ＯＲ^１０、－ＯＣ（Ｏ）Ｒ^９、－Ｃ（Ｏ）Ｎ（Ｒ^１０）_２、－ＯＣ（Ｏ）Ｎ（Ｒ^１０）_２、－ＮＲ^１０Ｃ（Ｏ）Ｎ（Ｒ^１０）_２、－ＮＲ^１０Ｃ（Ｏ）Ｒ^９、－ＮＲ^１０Ｃ（Ｏ）ＯＲ^９、Ｃ_１－６アルキル、－Ｃ_１－６アルキル－ＯＨ、－Ｃ_１－６アルキル－ＯＲ^９、－Ｃ_１－６アルキル－Ｎ（Ｒ^１０）_２、Ｃ_２－６アルケニル、Ｃ_２－６アルキニル、Ｃ_１－６ハロアルキル、Ｃ_３－８シクロアルキル、および－Ｃ_１－６アルキル－Ｃ_３－８シクロアルキルから選択され；
Ｒ^４は、

, Or a 5- or ⁶ -membered heteroaryl optionally substituted with one, two, or three R8 groups;
R ² is H, -OH, -N (R ¹⁰ ) ₂ , -NHS (O) ₂ R ⁹ , -S (O) ₂ N (R ¹⁰ ) ₂ , -C (O) N (R ¹⁰ ) ₂ , -OC (O) N (R ¹⁰ ) ₂ , -OC _1-6 alkyl, -C _1-6 alkyl-OH, -C _1-6 alkyl-OR ⁹ , -C _1-6 alkyl-N ( R ¹⁰ ) ₂ , C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _3-8 cycloalkyl;
R ³ are independently halogen, -CN, -OH, -OR ⁹ , -SR ⁹ , -N (R ¹⁰ ) ₂ , -NO ₂ , -S (O) R ⁹ , -S (O) ₂ . R ⁹ , -NHS (O) ₂ R ⁹ , -S (O) ₂ N (R ¹⁰ ) ₂ , -C (O) R ⁹ , -C (O) OR ¹⁰ , -OC (O) R ⁹ ,- C (O) N (R ¹⁰ ) ₂ , -OC (O) N (R ¹⁰ ) ₂ , -NR ¹⁰ C (O) N (R ¹⁰ ) ₂ , -NR ¹⁰ C (O) R ⁹ , -NR ¹⁰ C (O) OR ⁹ , C _1-6 alkyl, -C _1-6 alkyl-OH, -C _1-6 alkyl-OR ⁹ , -C _1-6 alkyl-N (R ¹⁰ ) ₂ , C _2-6 Selected from alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, and -C _1-6 alkyl-C _3-8 cycloalkyl;
^R4 is

であり；
Ｒ^５はそれぞれ独立して、ハロゲン、－ＣＮ、－ＯＨ、－ＯＲ^９、－ＳＲ^９、－Ｎ（Ｒ^１０）_２、－Ｓ（Ｏ）Ｒ^９、－Ｓ（Ｏ）_２Ｒ^９、－ＮＨＳ（Ｏ）_２Ｒ^９、－Ｓ（Ｏ）_２Ｎ（Ｒ^１０）_２、－Ｃ（Ｏ）ＮＨＳ（Ｏ）_２Ｎ（Ｒ^１０）_２、－Ｃ（Ｏ）Ｒ^９、－Ｃ（Ｏ）ＯＲ^１０、－ＯＣ（Ｏ）Ｒ^９、－Ｃ（Ｏ）Ｎ（Ｒ^１０）_２、－ＯＣ（Ｏ）Ｎ（Ｒ^１０）_２、－ＮＲ^１０Ｃ（Ｏ）Ｎ（Ｒ^１０）_２、－ＮＲ^１０Ｃ（Ｏ）Ｒ^９、－ＮＲ^１０Ｃ（Ｏ）ＯＲ^９、Ｃ_１－６アルキル、－Ｃ_１－６アルキル－Ｒ^９、－Ｃ_１－６アルキル－ＯＨ、－Ｃ_１－６アルキル－ＯＲ^９、－Ｃ_１－６アルキル－Ｎ（Ｒ^１０）_２、－Ｃ_１－６アルキル－Ｃ（Ｏ）ＯＲ^１０、Ｃ_２－６アルケニル、－Ｃ_２－６アルケニル－Ｃ（Ｏ）ＯＲ^１０、Ｃ_２－６アルキニル、Ｃ_１－６ハロアルキル、Ｃ_１－６ハロアルキル－ＯＨ、Ｃ_３－８シクロアルキル、－Ｃ_１－６アルキル－Ｃ_３－８シクロアルキル、フェニル、－Ｃ_１－６アルキル－フェニル、Ｃ_２－９ヘテロシクロアルキル、－Ｃ_１－６アルキル－Ｃ_２－９ヘテロシクロアルキル、およびＣ_１－９ヘテロアリールから選択され；ここで、Ｃ_３－８シクロアルキル、－Ｃ_１－６アルキル－Ｃ_３－８シクロアルキル、フェニル、－Ｃ_１－６アルキル－フェニル、およびＣ_１－９ヘテロアリールは、ハロゲン、－Ｃ（Ｏ）ＯＲ^１０、Ｃ_１－６アルキル、Ｃ_１－６ハロアルキル、Ｃ_３－８シクロアルキル、およびＣ_２－９ヘテロシクロアルキルから独立して選択される１つ、２つ、または３つの基で随意に置換され；ならびにここで、Ｃ_２－９ヘテロシクロアルキルおよび－Ｃ_１－６アルキル－Ｃ_２－９ヘテロシクロアルキルは、ハロゲン、－Ｃ（Ｏ）ＯＲ^１０、Ｃ_１－６アルキル、Ｃ_１－６ハロアルキル、およびオキソから独立して選択される１つ、２つ、または３つの基で随意に置換され；
Ｒ^６は、－Ｃ（Ｏ）ＯＲ^７、－Ｃ（Ｏ）ＮＨＳ（Ｏ）_２Ｎ（Ｒ^１０）_２、

And;
R ⁵ are independently halogen, -CN, -OH, -OR ⁹ , -SR ⁹ , -N (R ¹⁰ ) ₂ , -S (O) R ⁹ , -S (O) ₂ R ⁹ ,- NHS (O) ₂ R ⁹ , -S (O) ₂ N (R ¹⁰ ) ₂ , -C (O) NHS (O) ₂ N (R ¹⁰ ) ₂ , -C (O) R ⁹ , -C (O) ) OR ¹⁰ , -OC (O) R ⁹ , -C (O) N (R ¹⁰ ) ₂ , -OC (O) N (R ¹⁰ ) ₂ , -NR ¹⁰ C (O) N (R ¹⁰ ) ₂ , -NR ¹⁰ C (O) R ⁹ , -NR ¹⁰ C (O) OR ⁹ , C _1-6 alkyl, -C _1-6 alkyl-R ⁹ , -C _1-6 alkyl-OH, -C _1-6 Alkyl-OR ⁹ , -C _1-6 Alkyl-N (R ¹⁰ ) ₂ , -C _1-6 Alkyl-C (O) OR ¹⁰ , C _2-6 Alkenyl, -C _2-6 Alkenyl-C (O) OR ¹⁰ , C _2-6 alkynyl, C _1-6 haloalkyl, C _1-6 haloalkyl-OH, C _3-8 cycloalkyl, -C _1-6 alkyl-C _3-8 cycloalkyl, phenyl, -C _1- Selected from ₆ Alkyl-Phenyl, C _2-9 Heterocycloalkyl, -C _1-6 Alkyl-C _2-9 Heterocycloalkyl, and C _1-9 Heteroaryl; where C _3-8 Cycloalkyl,- C _1-6 alkyl-C _3-8 cycloalkyl, phenyl, -C _1-6 alkyl-phenyl, and C _1-9 heteroaryl are halogen, -C (O) OR ¹⁰ , C _1-6 alkyl, C. Arbitrarily substituted with one, two, or three groups independently selected from _1-6 haloalkyl, C _3-8 cycloalkyl, and C _2-9 heterocycloalkyl; and where C _{2- 9} Heterocycloalkyl and -C 1-6alkyl-C _2-9 Heterocycloalkyl are selected independently of halogen, -C (O) OR ¹⁰ , C _{1-6 alkyl, C 1-6 haloalkyl} , and oxo. It is optionally replaced with one, two, or three groups;
R ⁶ is -C (O) OR ⁷ , -C (O) NHS (O) ₂ N (R ¹⁰ ) ₂ ,

であり；
Ｒ^７は独立して、ＨおよびＣ_１－６アルキルから選択され；
Ｒ^８はそれぞれ独立して、ハロゲン、－ＯＨ、－ＯＲ^９、－Ｎ（Ｒ^１０）_２、－Ｓ（Ｏ）Ｒ^９、－Ｓ（Ｏ）_２Ｒ^９、－ＮＨＳ（Ｏ）_２Ｒ^９、－Ｓ（Ｏ）_２Ｎ（Ｒ^１０）_２、－Ｃ（Ｏ）ＮＨＳ（Ｏ）_２Ｎ（Ｒ^１０）_２、－Ｃ（Ｏ）Ｒ^９、－Ｃ（Ｏ）ＯＲ^１０、－ＯＣ（Ｏ）Ｒ^９、－Ｃ（Ｏ）Ｎ（Ｒ^１０）_２、－ＯＣ（Ｏ）Ｎ（Ｒ^１０）_２、－ＮＲ^１０Ｃ（Ｏ）Ｎ（Ｒ^１０）_２、－ＮＲ^１０Ｃ（Ｏ）Ｒ^９、－ＮＲ^１０Ｃ（Ｏ）ＯＲ^９、Ｃ_１－６アルキル、－Ｃ_１－６アルキル－ＯＨ、－Ｃ_１－６アルキル－ＯＲ^９、－Ｃ_１－６アルキル－Ｎ（Ｒ^１０）_２、－Ｃ_１－６アルキル－Ｃ（Ｏ）ＯＲ^１０、Ｃ_１－６ハロアルキル、Ｃ_１－６ハロアルキル－ＯＨ、Ｃ_３－８シクロアルキル、－Ｃ_１－６アルキル－Ｃ_３－８シクロアルキル、フェニル、－Ｃ_１－６アルキル－フェニル、Ｃ_２－９ヘテロシクロアルキル、およびＣ_１－９ヘテロアリールから選択され；ここで、フェニル、－Ｃ_１－６アルキル－フェニル、およびＣ_１－９ヘテロアリールは、ハロゲン、Ｃ_１－６アルキル、Ｃ_１－６ハロアルキル、Ｃ_３－８シクロアルキル、およびＣ_２－９ヘテロシクロアルキルから独立して選択される１つ、２つ、または３つの基で随意に置換され；ならびにここで、Ｃ_２－９ヘテロシクロアルキルは、ハロゲン、Ｃ_１－６アルキル、Ｃ_１－６ハロアルキル、およびオキソから独立して選択される１つ、２つ、または３つの基で随意に置換され；
Ｒ^９はそれぞれ独立して、Ｃ_１－６アルキル、Ｃ_１－６ハロアルキル、Ｃ_３－８シクロアルキル、－Ｃ_１－６アルキル－Ｃ_３－８シクロアルキル、フェニル、－Ｃ_１－６アルキル－フェニル、Ｃ_２－９ヘテロシクロアルキル、－Ｃ_１－６アルキル－Ｃ_２－９ヘテロシクロアルキル、Ｃ_２－９ヘテロアリール、および－Ｃ_１－６アルキル－Ｃ_２－９ヘテロアリールから選択され、ここで、Ｃ_１－６アルキル、フェニル、－Ｃ_１－６アルキル－フェニル、－Ｃ_１－６アルキル－Ｃ_２－９ヘテロシクロアルキル、Ｃ_２－９ヘテロアリール、および－Ｃ_１－６アルキル－Ｃ_２－９ヘテロアリールは、Ｃ_１－６アルキル、－ＯＲ^１１、－Ｎ（Ｒ^１１）_２、Ｃ_１－６アルキル、Ｃ_３－８シクロアルキル、－Ｎ（Ｒ^１１）Ｃ（Ｏ）Ｒ^１２、－Ｃ（Ｏ）Ｒ^１２、および－Ｃ（Ｏ）ＯＲ^１２から独立して選択される１つまたは２つの基で随意に置換され；
Ｒ^１０はそれぞれ独立して、Ｈ、Ｃ_１－６アルキル、Ｃ_１－６ハロアルキル、Ｃ_３－８シクロアルキル、－Ｃ_１－６アルキル－Ｃ_３－８シクロアルキル、フェニル、－Ｃ_１－６アルキル－フェニル、およびＣ_２－９ヘテロアリールから選択され、ここで、Ｃ_１－６アルキル、フェニル、－Ｃ_１－６アルキル－フェニル、およびＣ_２－９ヘテロアリールは、ハロゲン、Ｃ_１－６アルキル、－Ｎ（Ｒ^１１）_２、および－Ｃ（Ｏ）ＯＲ^１２から独立して選択される１つまたは２つの基で随意に置換され；あるいは、２つのＲ^１０、およびそれらが結合している窒素原子は一緒になって、Ｃ_１－６アルキル、オキソ、および－Ｃ（Ｏ）ＯＨから独立して選択される１つ、２つ、または３つの基で随意に置換された５員または６員のヘテロシクロアルキル環を形成し；
Ｒ^１１はそれぞれ独立して、ＨおよびＣ_１－６アルキルから選択され；
Ｒ^１２はそれぞれ独立して、ＨおよびＣ_１－６アルキルから選択され；
Ｒ^１３はそれぞれ独立して、Ｃ_１－６アルキルから選択され；
ｍは、１、２、３、または４であり；
ｎは、０、１、２、または３であり；
ｐは、０、１、２、３、４、または５であり；および、
ｑは、０、１、２、３、または４である。

And;
^R7 is independently selected from H and C _1-6 alkyl;
R ⁸ are independently halogen, -OH, -OR ⁹ , -N (R ¹⁰ ) ₂ , -S (O) R ⁹ , -S (O) ₂ R ⁹ , -NHS (O) ₂ R ⁹ , -S (O) ₂ N (R ¹⁰ ) ₂ , -C (O) NHS (O) ₂ N (R ¹⁰ ) ₂ , -C (O) R ⁹ , -C (O) OR ¹⁰ , -OC ( O) R ⁹ , -C (O) N (R ¹⁰ ) ₂ , -OC (O) N (R ¹⁰ ) ₂ , -NR ¹⁰ C (O) N (R ¹⁰ ) ₂ , -NR ¹⁰ C (O) R ⁹ , -NR ¹⁰ C (O) OR ⁹ , C _1-6 alkyl, -C _1-6 alkyl-OH, -C _1-6 alkyl-OR ⁹ , -C _1-6 alkyl-N (R ¹⁰ ) ₂ , -C _1-6 alkyl-C (O) OR ¹⁰ , C _1-6 haloalkyl, C _1-6 haloalkyl-OH, C _3-8 cycloalkyl, -C _1-6 alkyl-C _3-8 cycloalkyl , Phenyl, -C _1-6 alkyl-phenyl, C _2-9 heterocycloalkyl, and C _1-9 heteroaryl; where phenyl, -C _1-6 alkyl-phenyl, and C _1-9 Heteroaryl is one, two or three groups independently selected from halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, and C _2-9 heterocycloalkyl. And where the C _2-9 heterocycloalkyl is selected independently of halogen, C _1-6 alkyl, C _1-6 haloalkyl, and oxo, one, two, or three. Arbitrarily replaced by one group;
R ⁹ are independently C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, -C _1-6 alkyl-C _3-8 cycloalkyl, phenyl, -C _1-6 alkyl- Selected from phenyl, C _2-9 heterocycloalkyl, -C _1-6 alkyl-C _2-9 heterocycloalkyl, C _2-9 heteroaryl, and -C _1-6 alkyl-C _2-9 heteroaryl, Here, C _1-6 alkyl, phenyl, -C _1-6 alkyl-phenyl, -C _1-6 alkyl-C _2-9 heterocycloalkyl, C _2-9 heteroaryl, and -C _1-6 alkyl- C _2-9 heteroaryls are C _1-6 alkyl, -OR ¹¹ , -N (R ¹¹ ) ₂ , C _1-6 alkyl, C _3-8 cycloalkyl, -N (R ¹¹ ) C (O) R. ¹² ; optionally substituted with one or two groups independently selected from -C (O) R ¹² and -C (O) OR ¹² ;
R ¹⁰ are independently H, C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, -C _1-6 alkyl-C _3-8 cycloalkyl, phenyl, -C _1-6 . Selected from alkyl-phenyl and C _2-9 heteroaryl, where C _1-6 alkyl, phenyl, -C _1-6 alkyl-phenyl, and C _2-9 heteroaryl are halogen, C _1-6 . It is optionally substituted with one or two groups independently selected from alkyl, -N (R ¹¹ ) ₂ , and -C (O) OR ¹² ; or two R ^10s , and they are combined. The nitrogen atoms present together are 5-membered or optionally substituted with one, two, or three groups independently selected from C _1-6 alkyl, oxo, and -C (O) OH. Forming a 6-membered heterocycloalkyl ring;
R ¹¹ is independently selected from H and C _1-6 alkyl;
^R12 is independently selected from H and C _1-6 alkyl;
Each R ¹³ is independently selected from C _1-6 alkyl;
m is 1, 2, 3, or 4;
n is 0, 1, 2, or 3;
p is 0, 1, 2, 3, 4, or 5; and
q is 0, 1, 2, 3, or 4.

In another aspect, a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, is provided herein.

式中、
Ｒ^１は、－ＣＨ_２Ｒ^４、－ＣＮ、－Ｂ（ＯＨ）_２、－Ｎ（Ｒ^１０）_２、－ＮＲ^１０Ｃ（Ｏ）Ｒ^９、－Ｃ（Ｏ）ＯＨ、－ＣＨ_２Ｃ（Ｏ）ＯＨ、－Ｃ（Ｏ）Ｎ（Ｒ^１０）_２、－Ｃ（Ｏ）ＮＨＳ（Ｏ）_２Ｎ（Ｒ^１０）_２、－Ｃ_１－６アルキル－ＯＨ、Ｃ_３－８シクロアルキル、

During the ceremony
R ¹ is -CH ₂ R ⁴ , -CN, -B (OH) ₂ , -N (R ¹⁰ ) ₂ , -NR ¹⁰ C (O) R ⁹ , -C (O) OH, -CH ₂ C ( O) OH, -C (O) N (R ¹⁰ ) ₂ , -C (O) NHS (O) ₂ N (R ¹⁰ ) ₂ , -C _1-6 alkyl-OH, C _3-8 cycloalkyl,

、あるいは１つ、２つ、または３つのＲ^８基で随意に置換された５員または６員のヘテロアリールであり；
Ｒ^２は、Ｈ、－ＯＨ、－Ｎ（Ｒ^１０）_２、－ＮＨＳ（Ｏ）_２Ｒ^９、－Ｓ（Ｏ）_２Ｎ（Ｒ^１０）_２、－Ｃ（Ｏ）Ｎ（Ｒ^１０）_２、－ＯＣ（Ｏ）Ｎ（Ｒ^１０）_２、－Ｏ－Ｃ_１－６アルキル、－Ｃ_１－６アルキル－ＯＨ、－Ｃ_１－６アルキル－ＯＲ^９、－Ｃ_１－６アルキル－Ｎ（Ｒ^１０）_２、Ｃ_２－６アルケニル、Ｃ_２－６アルキニル、Ｃ_１－６ハロアルキル、Ｃ_３－８シクロアルキルであり；
Ｒ^３はそれぞれ独立して、ハロゲン、－ＣＮ、－ＯＨ、－ＯＲ^９、－ＳＲ^９、－Ｎ（Ｒ^１０）_２、－Ｓ（Ｏ）Ｒ^９、－Ｓ（Ｏ）_２Ｒ^９、－ＮＨＳ（Ｏ）_２Ｒ^９、－Ｓ（Ｏ）_２Ｎ（Ｒ^１０）_２、－Ｃ（Ｏ）Ｒ^９、－Ｃ（Ｏ）ＯＲ^１０、－ＯＣ（Ｏ）Ｒ^９、－Ｃ（Ｏ）Ｎ（Ｒ^１０）_２、－ＯＣ（Ｏ）Ｎ（Ｒ^１０）_２、－ＮＲ^１０Ｃ（Ｏ）Ｎ（Ｒ^１０）_２、－ＮＲ^１０Ｃ（Ｏ）Ｒ^９、－ＮＲ^１０Ｃ（Ｏ）ＯＲ^９、Ｃ_１－６アルキル、－Ｃ_１－６アルキル－ＯＨ、－Ｃ_１－６アルキル－ＯＲ^９、－Ｃ_１－６アルキル－Ｎ（Ｒ^１０）_２、Ｃ_２－６アルケニル、Ｃ_２－６アルキニル、Ｃ_１－６ハロアルキル、Ｃ_３－８シクロアルキル、および－Ｃ_１－６アルキル－Ｃ_３－８シクロアルキルから選択され；
Ｒ^４は、

, Or a 5- or ⁶ -membered heteroaryl optionally substituted with one, two, or three R8 groups;
R ² is H, -OH, -N (R ¹⁰ ) ₂ , -NHS (O) ₂ R ⁹ , -S (O) ₂ N (R ¹⁰ ) ₂ , -C (O) N (R ¹⁰ ) ₂ , -OC (O) N (R ¹⁰ ) ₂ , -OC _1-6 alkyl, -C _1-6 alkyl-OH, -C _1-6 alkyl-OR ⁹ , -C _1-6 alkyl-N ( R ¹⁰ ) ₂ , C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _3-8 cycloalkyl;
R ³ are independently halogen, -CN, -OH, -OR ⁹ , -SR ⁹ , -N (R ¹⁰ ) ₂ , -S (O) R ⁹ , -S (O) ₂ R ⁹ ,- NHS (O) ₂ R ⁹ , -S (O) ₂ N (R ¹⁰ ) ₂ , -C (O) R ⁹ , -C (O) OR ¹⁰ , -OC (O) R ⁹ , -C (O) N (R ¹⁰ ) ₂ , -OC (O) N (R ¹⁰ ) ₂ , -NR ¹⁰ C (O) N (R ¹⁰ ) ₂ , -NR ¹⁰ C (O) R ⁹ , -NR ¹⁰ C (O) OR ⁹ , C _1-6 alkyl, -C _1-6 alkyl-OH, -C _1-6 alkyl-OR ⁹ , -C _1-6 alkyl-N (R ¹⁰ ) ₂ , C _2-6 alkenyl, C ₂ Selected from _-6 alkynyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, and -C _1-6 alkyl-C _3-8 cycloalkyl;
^R4 is

であり；
Ｒ^５はそれぞれ独立して、ハロゲン、－ＣＮ、－ＯＨ、－ＯＲ^９、－ＳＲ^９、－Ｎ（Ｒ^１０）_２、－Ｓ（Ｏ）Ｒ^９、－Ｓ（Ｏ）_２Ｒ^９、－ＮＨＳ（Ｏ）_２Ｒ^９、－Ｓ（Ｏ）_２Ｎ（Ｒ^１０）_２、－Ｃ（Ｏ）ＮＨＳ（Ｏ）_２Ｎ（Ｒ^１０）_２、－Ｃ（Ｏ）Ｒ^９、－Ｃ（Ｏ）ＯＲ^１０、－ＯＣ（Ｏ）Ｒ^９、－Ｃ（Ｏ）Ｎ（Ｒ^１０）_２、－ＯＣ（Ｏ）Ｎ（Ｒ^１０）_２、－ＮＲ^１０Ｃ（Ｏ）Ｎ（Ｒ^１０）_２、－ＮＲ^１０Ｃ（Ｏ）Ｒ^９、－ＮＲ^１０Ｃ（Ｏ）ＯＲ^９、Ｃ_１－６アルキル、－Ｃ_１－６アルキル－Ｒ^９、－Ｃ_１－６アルキル－ＯＨ、－Ｃ_１－６アルキル－ＯＲ^９、－Ｃ_１－６アルキル－Ｎ（Ｒ^１０）_２、－Ｃ_１－６アルキル－Ｃ（Ｏ）ＯＲ^１０、Ｃ_２－６アルケニル、－Ｃ_２－６アルケニル－Ｃ（Ｏ）ＯＲ^１０、Ｃ_２－６アルキニル、Ｃ_１－６ハロアルキル、Ｃ_１－６ハロアルキル－ＯＨ、Ｃ_３－８シクロアルキル、－Ｃ_１－６アルキル－Ｃ_３－８シクロアルキル、フェニル、－Ｃ_１－６アルキル－フェニル、Ｃ_２－９ヘテロシクロアルキル、およびＣ_１－９ヘテロアリールから選択され；ここで、フェニル、－Ｃ_１－６アルキル－フェニル、およびＣ_１－９ヘテロアリールは、ハロゲン、Ｃ_１－６アルキル、Ｃ_１－６ハロアルキル、Ｃ_３－８シクロアルキル、およびＣ_２－９ヘテロシクロアルキルから独立して選択される１つ、２つ、または３つの基で随意に置換され；ならびにここで、Ｃ_２－９ヘテロシクロアルキルは、ハロゲン、Ｃ_１－６アルキル、Ｃ_１－６ハロアルキル、およびオキソから独立して選択される１つ、２つ、または３つの基で随意に置換され；
Ｒ^６は、－Ｃ（Ｏ）ＯＲ^７、－Ｃ（Ｏ）ＮＨＳ（Ｏ）_２Ｎ（Ｒ^１０）_２、

And;
R ⁵ are independently halogen, -CN, -OH, -OR ⁹ , -SR ⁹ , -N (R ¹⁰ ) ₂ , -S (O) R ⁹ , -S (O) ₂ R ⁹ ,- NHS (O) ₂ R ⁹ , -S (O) ₂ N (R ¹⁰ ) ₂ , -C (O) NHS (O) ₂ N (R ¹⁰ ) ₂ , -C (O) R ⁹ , -C (O) ) OR ¹⁰ , -OC (O) R ⁹ , -C (O) N (R ¹⁰ ) ₂ , -OC (O) N (R ¹⁰ ) ₂ , -NR ¹⁰ C (O) N (R ¹⁰ ) ₂ , -NR ¹⁰ C (O) R ⁹ , -NR ¹⁰ C (O) OR ⁹ , C _1-6 alkyl, -C _1-6 alkyl-R ⁹ , -C _1-6 alkyl-OH, -C _1-6 Alkyl-OR ⁹ , -C _1-6 Alkyl-N (R ¹⁰ ) ₂ , -C _1-6 Alkyl-C (O) OR ¹⁰ , C _2-6 Alkenyl, -C _2-6 Alkenyl-C (O) OR ¹⁰ , C _2-6 alkynyl, C _1-6 haloalkyl, C _1-6 haloalkyl-OH, C _3-8 cycloalkyl, -C _1-6 alkyl-C _3-8 cycloalkyl, phenyl, -C _1- Selected from ₆ Alkyl-Phenyl, C _2-9 Heterocycloalkyl, and C _1-9 Heteroaryl; where phenyl, -C _1-6 Alkyl-Phenyl, and C _1-9 Heteroaryl are halogens, C. Arbitrarily substituted with one, two, or three groups independently selected from _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, and C _2-9 heterocycloalkyl; and Here, the C _2-9 heterocycloalkyl is optionally substituted with one, two, or three groups independently selected from halogen, C _1-6 alkyl, C _1-6 haloalkyl, and oxo. ;
R ⁶ is -C (O) OR ⁷ , -C (O) NHS (O) ₂ N (R ¹⁰ ) ₂ ,

であり；
Ｒ^７はそれぞれ独立して、ＨおよびＣ_１－６アルキルから選択され；
Ｒ^８はそれぞれ独立して、ハロゲン、－ＯＨ、－ＯＲ^９、－Ｎ（Ｒ^１０）_２、－Ｓ（Ｏ）Ｒ^９、－Ｓ（Ｏ）_２Ｒ^９、－ＮＨＳ（Ｏ）_２Ｒ^９、－Ｓ（Ｏ）_２Ｎ（Ｒ^１０）_２、－Ｃ（Ｏ）ＮＨＳ（Ｏ）_２Ｎ（Ｒ^１０）_２、－Ｃ（Ｏ）Ｒ^９、－Ｃ（Ｏ）ＯＲ^１０、－ＯＣ（Ｏ）Ｒ^９、－Ｃ（Ｏ）Ｎ（Ｒ^１０）_２、－ＯＣ（Ｏ）Ｎ（Ｒ^１０）_２、－ＮＲ^１０Ｃ（Ｏ）Ｎ（Ｒ^１０）_２、－ＮＲ^１０Ｃ（Ｏ）Ｒ^９、－ＮＲ^１０Ｃ（Ｏ）ＯＲ^９、Ｃ_１－６アルキル、－Ｃ_１－６アルキル－ＯＨ、－Ｃ_１－６アルキル－ＯＲ^９、－Ｃ_１－６アルキル－Ｎ（Ｒ^１０）_２、－Ｃ_１－６アルキル－Ｃ（Ｏ）ＯＲ^１０、Ｃ_１－６ハロアルキル、Ｃ_１－６ハロアルキル－ＯＨ、Ｃ_３－８シクロアルキル、－Ｃ_１－６アルキル－Ｃ_３－８シクロアルキル、フェニル、－Ｃ_１－６アルキル－フェニル、Ｃ_２－９ヘテロシクロアルキル、およびＣ_１－９ヘテロアリールから選択され；ここで、フェニル、－Ｃ_１－６アルキル－フェニル、およびＣ_１－９ヘテロアリールは、ハロゲン、Ｃ_１－６アルキル、Ｃ_１－６ハロアルキル、Ｃ_３－８シクロアルキル、およびＣ_２－９ヘテロシクロアルキルから独立して選択される１つ、２つ、または３つの基で随意に置換され；ならびにここで、Ｃ_２－９ヘテロシクロアルキルは、ハロゲン、Ｃ_１－６アルキル、Ｃ_１－６ハロアルキル、およびオキソから独立して選択される１つ、２つ、または３つの基で随意に置換され；
Ｒ^９はそれぞれ独立して、Ｃ_１－６アルキル、Ｃ_１－６ハロアルキル、Ｃ_３－８シクロアルキル、－Ｃ_１－６アルキル－Ｃ_３－８シクロアルキル、フェニル、－Ｃ_１－６アルキル－フェニル、Ｃ_２－９ヘテロシクロアルキル、－Ｃ_１－６アルキル－Ｃ_２－９ヘテロシクロアルキル、Ｃ_２－９ヘテロアリール、および－Ｃ_１－６アルキル－Ｃ_２－９ヘテロアリールから選択され、ここで、Ｃ_１－６アルキル、フェニル、－Ｃ_１－６アルキル－フェニル、－Ｃ_１－６アルキル－Ｃ_２－９ヘテロシクロアルキル、Ｃ_２－９ヘテロアリール、および－Ｃ_１－６アルキル－Ｃ_２－９ヘテロアリールは、Ｃ_１－６アルキル、－ＯＲ１１、－Ｎ（Ｒ^１１）_２、Ｃ_１－６アルキル、Ｃ_３－８シクロアルキル、－Ｎ（Ｒ^１１）Ｃ（Ｏ）Ｒ^１２、－Ｃ（Ｏ）Ｒ^１２、および－Ｃ（Ｏ）ＯＲ^１２から独立して選択される１つまたは２つの基で随意に置換され；
Ｒ^１０はそれぞれ独立して、Ｈ、Ｃ_１－６アルキル、Ｃ_１－６ハロアルキル、Ｃ_３－８シクロアルキル、－Ｃ_１－６アルキル－Ｃ_３－８シクロアルキル、フェニル、－Ｃ_１－６アルキル－フェニル、およびＣ_２－９ヘテロアリールから選択され、ここで、Ｃ_１－６アルキル、フェニル、－Ｃ_１－６アルキル－フェニル、およびＣ_２－９ヘテロアリールは、ハロゲン、Ｃ_１－６アルキル、－Ｎ（Ｒ^１１）_２、および－Ｃ（Ｏ）ＯＲ^１２から独立して選択される１つまたは２つの基で随意に置換され；あるいは、２つのＲ^１０、およびそれらが結合している窒素原子は一緒になって、Ｃ_１－６アルキル、オキソ、および－Ｃ（Ｏ）ＯＨから独立して選択される１つ、２つ、または３つの基で随意に置換された５員または６員のヘテロシクロアルキル環を形成し；
Ｒ^１１はそれぞれ独立して、ＨおよびＣ_１－６アルキルから選択され；
Ｒ^１２は独立して、ＨおよびＣ_１－６アルキルから選択され；
ｎは、０、１、２、または３であり；
ｐは、０、１、２、３、４、または５であり；
ｑは、０、１、２、３、または４である。

And;
^R7 is independently selected from H and C _1-6 alkyl;
R ⁸ are independently halogen, -OH, -OR ⁹ , -N (R ¹⁰ ) ₂ , -S (O) R ⁹ , -S (O) ₂ R ⁹ , -NHS (O) ₂ R ⁹ , -S (O) ₂ N (R ¹⁰ ) ₂ , -C (O) NHS (O) ₂ N (R ¹⁰ ) ₂ , -C (O) R ⁹ , -C (O) OR ¹⁰ , -OC ( O) R ⁹ , -C (O) N (R ¹⁰ ) ₂ , -OC (O) N (R ¹⁰ ) ₂ , -NR ¹⁰ C (O) N (R ¹⁰ ) ₂ , -NR ¹⁰ C (O) R ⁹ , -NR ¹⁰ C (O) OR ⁹ , C _1-6 alkyl, -C _1-6 alkyl-OH, -C _1-6 alkyl-OR ⁹ , -C _1-6 alkyl-N (R ¹⁰ ) ₂ , -C _1-6 alkyl-C (O) OR ¹⁰ , C _1-6 haloalkyl, C _1-6 haloalkyl-OH, C _3-8 cycloalkyl, -C _1-6 alkyl-C _3-8 cycloalkyl , Phenyl, -C _1-6 alkyl-phenyl, C _2-9 heterocycloalkyl, and C _1-9 heteroaryl; where phenyl, -C _1-6 alkyl-phenyl, and C _1-9 Heteroaryl is one, two or three groups independently selected from halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, and C _2-9 heterocycloalkyl. And where C _2-9 heterocycloalkyl is selected independently of halogen, C _1-6 alkyl, C _1-6 haloalkyl, and oxo, one, two, or three. Arbitrarily replaced by one group;
R ⁹ are independently C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, -C _1-6 alkyl-C _3-8 cycloalkyl, phenyl, -C _1-6 alkyl- Selected from phenyl, C _2-9 heterocycloalkyl, -C _1-6 alkyl-C _2-9 heterocycloalkyl, C _2-9 heteroaryl, and -C _1-6 alkyl-C _2-9 heteroaryl, Here, C _1-6 alkyl, phenyl, -C _1-6 alkyl-phenyl, -C _1-6 alkyl-C _2-9 heterocycloalkyl, C _2-9 heteroaryl, and -C _1-6 alkyl- C _2-9 heteroaryls are C _1-6 alkyl, -OR 11, -N (R ¹¹ ) ₂ , C _1-6 alkyl, C _3-8 cycloalkyl, -N (R ¹¹ ) C (O) R ¹² , -C (O) R ¹² , and -C (O) OR ¹² optionally substituted with one or two groups selected independently;
R ¹⁰ are independently H, C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, -C _1-6 alkyl-C _3-8 cycloalkyl, phenyl, -C _1-6 . Selected from alkyl-phenyl and C _2-9 heteroaryl, where C _1-6 alkyl, phenyl, -C _1-6 alkyl-phenyl, and C _2-9 heteroaryl are halogen, C _1-6 . It is optionally substituted with one or two groups independently selected from alkyl, -N (R ¹¹ ) ₂ , and -C (O) OR ¹² ; or two R ^10s , and they are combined. The nitrogen atoms present together are 5-membered or optionally substituted with one, two, or three groups independently selected from C _1-6 alkyl, oxo, and -C (O) OH. Forming a 6-membered heterocycloalkyl ring;
R ¹¹ is independently selected from H and C _1-6 alkyl;
^R12 is independently selected from H and C _1-6 alkyl;
n is 0, 1, 2, or 3;
p is 0, 1, 2, 3, 4, or 5;
q is 0, 1, 2, 3, or 4.

In another aspect, a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, is provided herein.

式中、
Ｒ^１は、－ＣＨ_２Ｒ^４、－ＣＮ、－Ｂ（ＯＨ）_２、－Ｎ（Ｒ^１０）_２、－ＮＲ^１０Ｃ（Ｏ）Ｒ^９、－Ｃ（Ｏ）ＯＨ、－ＣＨ_２Ｃ（Ｏ）ＯＨ、－Ｃ（Ｏ）Ｎ（Ｒ^１０）_２、－Ｃ（Ｏ）ＮＨＳ（Ｏ）_２Ｎ（Ｒ^１０）_２、－Ｃ_１－６アルキル－ＯＨ、Ｃ_３－８シクロアルキル、

During the ceremony
R ¹ is -CH ₂ R ⁴ , -CN, -B (OH) ₂ , -N (R ¹⁰ ) ₂ , -NR ¹⁰ C (O) R ⁹ , -C (O) OH, -CH ₂ C ( O) OH, -C (O) N (R ¹⁰ ) ₂ , -C (O) NHS (O) ₂ N (R ¹⁰ ) ₂ , -C _1-6 alkyl-OH, C _3-8 cycloalkyl,

、あるいは１つ、２つ、または３つのＲ^８基で随意に置換された５員または６員のヘテロアリールであり；
Ｒ^２は、Ｈ、－ＯＨ、－Ｎ（Ｒ^１０）_２、－ＮＨＳ（Ｏ）_２Ｒ^９、－Ｓ（Ｏ）_２Ｎ（Ｒ^１０）_２、－Ｃ（Ｏ）Ｎ（Ｒ^１０）_２、－ＯＣ（Ｏ）Ｎ（Ｒ^１０）_２、－Ｏ－Ｃ_１－６アルキル、－Ｃ_１－６アルキル－ＯＨ、－Ｃ_１－６アルキル－ＯＲ^９、－Ｃ_１－６アルキル－Ｎ（Ｒ^１０）_２、Ｃ_２－６アルケニル、Ｃ_２－６アルキニル、Ｃ_１－６ハロアルキル、Ｃ_３－８シクロアルキルであり；
Ｒ^３はそれぞれ独立して、ハロゲン、－ＣＮ、－ＯＨ、－ＯＲ^９、－ＳＲ^９、－Ｎ（Ｒ^１０）_２、－Ｓ（Ｏ）Ｒ^９、－Ｓ（Ｏ）_２Ｒ^９、－ＮＨＳ（Ｏ）_２Ｒ^９、－Ｓ（Ｏ）_２Ｎ（Ｒ^１０）_２、－Ｃ（Ｏ）Ｒ^９、－Ｃ（Ｏ）ＯＲ^１０、－ＯＣ（Ｏ）Ｒ^９、－Ｃ（Ｏ）Ｎ（Ｒ^１０）_２、－ＯＣ（Ｏ）Ｎ（Ｒ^１０）_２、－ＮＲ^１０Ｃ（Ｏ）Ｎ（Ｒ^１０）_２、－ＮＲ^１０Ｃ（Ｏ）Ｒ^９、－ＮＲ^１０Ｃ（Ｏ）ＯＲ^９、Ｃ_１－６アルキル、－Ｃ_１－６アルキル－ＯＨ、－Ｃ_１－６アルキル－ＯＲ^９、－Ｃ_１－６アルキル－Ｎ（Ｒ^１０）_２、Ｃ_２－６アルケニル、Ｃ_２－６アルキニル、Ｃ_１－６ハロアルキル、Ｃ_３－８シクロアルキル、および－Ｃ_１－６アルキル－Ｃ_３－８シクロアルキルから選択され；
Ｒ^４は、

, Or a 5- or ⁶ -membered heteroaryl optionally substituted with one, two, or three R8 groups;
R ² is H, -OH, -N (R ¹⁰ ) ₂ , -NHS (O) ₂ R ⁹ , -S (O) ₂ N (R ¹⁰ ) ₂ , -C (O) N (R ¹⁰ ) ₂ , -OC (O) N (R ¹⁰ ) ₂ , -OC _1-6 alkyl, -C _1-6 alkyl-OH, -C _1-6 alkyl-OR ⁹ , -C _1-6 alkyl-N ( R ¹⁰ ) ₂ , C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _3-8 cycloalkyl;
R ³ are independently halogen, -CN, -OH, -OR ⁹ , -SR ⁹ , -N (R ¹⁰ ) ₂ , -S (O) R ⁹ , -S (O) ₂ R ⁹ ,- NHS (O) ₂ R ⁹ , -S (O) ₂ N (R ¹⁰ ) ₂ , -C (O) R ⁹ , -C (O) OR ¹⁰ , -OC (O) R ⁹ , -C (O) N (R ¹⁰ ) ₂ , -OC (O) N (R ¹⁰ ) ₂ , -NR ¹⁰ C (O) N (R ¹⁰ ) ₂ , -NR ¹⁰ C (O) R ⁹ , -NR ¹⁰ C (O) OR ⁹ , C _1-6 alkyl, -C _1-6 alkyl-OH, -C _1-6 alkyl-OR ⁹ , -C _1-6 alkyl-N (R ¹⁰ ) ₂ , C _2-6 alkenyl, C ₂ Selected from _-6 alkynyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, and -C _1-6 alkyl-C _3-8 cycloalkyl;
^R4 is

であり；
Ｒ^５はそれぞれ独立して、ハロゲン、－ＣＮ、－ＯＨ、－ＯＲ^９、－ＳＲ^９、－Ｎ（Ｒ^１０）_２、－Ｓ（Ｏ）Ｒ^９、－Ｓ（Ｏ）_２Ｒ^９、－ＮＨＳ（Ｏ）_２Ｒ^９、－Ｓ（Ｏ）_２Ｎ（Ｒ^１０）_２、－Ｃ（Ｏ）ＮＨＳ（Ｏ）_２Ｎ（Ｒ^１０）_２、－Ｃ（Ｏ）Ｒ^９、－Ｃ（Ｏ）ＯＲ^１０、－ＯＣ（Ｏ）Ｒ^９、－Ｃ（Ｏ）Ｎ（Ｒ^１０）_２、－ＯＣ（Ｏ）Ｎ（Ｒ^１０）_２、－ＮＲ^１０Ｃ（Ｏ）Ｎ（Ｒ^１０）_２、－ＮＲ^１０Ｃ（Ｏ）Ｒ^９、－ＮＲ^１０Ｃ（Ｏ）ＯＲ^９、Ｃ_１－６アルキル、－Ｃ_１－６アルキル－ＯＨ、－Ｃ_１－６アルキル－ＯＲ^９、－Ｃ_１－６アルキル－Ｎ（Ｒ^１０）_２、－Ｃ_１－６アルキル－Ｃ（Ｏ）ＯＲ^１０、Ｃ_２－６アルケニル、Ｃ_２－６アルキニル、Ｃ_１－６ハロアルキル、Ｃ_１－６ハロアルキル－ＯＨ、Ｃ_３－８シクロアルキル、－Ｃ_１－６アルキル－Ｃ_３－８シクロアルキル、フェニル、－Ｃ_１－６アルキル－フェニル、Ｃ_２－９ヘテロシクロアルキル、およびＣ_１－９ヘテロアリールから選択され；ここで、フェニル、－Ｃ_１－６アルキル－フェニル、およびＣ_１－９ヘテロアリールは、ハロゲン、Ｃ_１－６アルキル、Ｃ_１－６ハロアルキル、Ｃ_３－８シクロアルキル、およびＣ_２－９ヘテロシクロアルキルから独立して選択される１つ、２つ、または３つの基で随意に置換され；ならびにここで、Ｃ_２－９ヘテロシクロアルキルは、ハロゲン、Ｃ_１－６アルキル、Ｃ_１－６ハロアルキル、およびオキソから独立して選択される１つ、２つ、または３つの基で随意に置換され；
Ｒ^６は、－Ｃ（Ｏ）ＯＲ^７、－Ｃ（Ｏ）ＮＨＳ（Ｏ）_２Ｎ（Ｒ^１０）_２、

And;
R ⁵ are independently halogen, -CN, -OH, -OR ⁹ , -SR ⁹ , -N (R ¹⁰ ) ₂ , -S (O) R ⁹ , -S (O) ₂ R ⁹ ,- NHS (O) ₂ R ⁹ , -S (O) ₂ N (R ¹⁰ ) ₂ , -C (O) NHS (O) ₂ N (R ¹⁰ ) ₂ , -C (O) R ⁹ , -C (O) ) OR ¹⁰ , -OC (O) R ⁹ , -C (O) N (R ¹⁰ ) ₂ , -OC (O) N (R ¹⁰ ) ₂ , -NR ¹⁰ C (O) N (R ¹⁰ ) ₂ , -NR ¹⁰ C (O) R ⁹ , -NR ¹⁰ C (O) OR ⁹ , C _1-6 alkyl, -C _1-6 alkyl-OH, -C _1-6 alkyl-OR ⁹ , -C _1-6 Alkyl-N (R ¹⁰ ) ₂ , -C _1-6 alkyl-C (O) OR ¹⁰ , C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _1-6 haloalkyl-OH, C Selected from _3-8 cycloalkyl, -C _1-6 alkyl-C _3-8 cycloalkyl, phenyl, -C _1-6 alkyl-phenyl, C _2-9 heterocycloalkyl, and C _1-9 heteroaryl; Here, phenyl, -C _1-6 alkyl-phenyl, and C _1-9 heteroaryl are halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, and C _2-9 hetero. It is optionally substituted with one, two, or three groups independently selected from cycloalkyl; and where C _2-9 heterocycloalkyl is halogen, C _1-6 alkyl, C _1-6 . Arbitrarily substituted with one, two, or three groups independently selected from haloalkyl, and oxo;
R ⁶ is -C (O) OR ⁷ , -C (O) NHS (O) ₂ N (R ¹⁰ ) ₂ ,

であり；
Ｒ^７はそれぞれ独立して、ＨおよびＣ_１－６アルキルから選択され；
Ｒ^８はそれぞれ独立して、ハロゲン、－ＯＨ、－ＯＲ^９、－Ｎ（Ｒ^１０）_２、－Ｓ（Ｏ）Ｒ^９、－Ｓ（Ｏ）_２Ｒ^９、－ＮＨＳ（Ｏ）_２Ｒ^９、－Ｓ（Ｏ）_２Ｎ（Ｒ^１０）_２、－Ｃ（Ｏ）ＮＨＳ（Ｏ）_２Ｎ（Ｒ^１０）_２、－Ｃ（Ｏ）Ｒ^９、－Ｃ（Ｏ）ＯＲ^１０、－ＯＣ（Ｏ）Ｒ^９、－Ｃ（Ｏ）Ｎ（Ｒ^１０）_２、－ＯＣ（Ｏ）Ｎ（Ｒ^１０）_２、－ＮＲ^１０Ｃ（Ｏ）Ｎ（Ｒ^１０）_２、－ＮＲ^１０Ｃ（Ｏ）Ｒ^９、－ＮＲ^１０Ｃ（Ｏ）ＯＲ^９、Ｃ_１－６アルキル、－Ｃ_１－６アルキル－ＯＨ、－Ｃ_１－６アルキル－ＯＲ^９、－Ｃ_１－６アルキル－Ｎ（Ｒ^１０）_２、－Ｃ_１－６アルキル－Ｃ（Ｏ）ＯＲ^１０、Ｃ_１－６ハロアルキル、Ｃ_１－６ハロアルキル－ＯＨ、Ｃ_３－８シクロアルキル、－Ｃ_１－６アルキル－Ｃ_３－８シクロアルキル、フェニル、－Ｃ_１－６アルキル－フェニル、Ｃ_２－９ヘテロシクロアルキル、およびＣ_１－９ヘテロアリールから選択され；ここで、フェニル、－Ｃ_１－６アルキル－フェニル、およびＣ_１－９ヘテロアリールは、ハロゲン、Ｃ_１－６アルキル、Ｃ_１－６ハロアルキル、Ｃ_３－８シクロアルキル、およびＣ_２－９ヘテロシクロアルキルから独立して選択される１つ、２つ、または３つの基で随意に置換され；ならびにここで、Ｃ_２－９ヘテロシクロアルキルは、ハロゲン、Ｃ_１－６アルキル、Ｃ_１－６ハロアルキル、およびオキソから独立して選択される１つ、２つ、または３つの基で随意に置換され；
Ｒ^９はそれぞれ独立して、Ｃ_１－６アルキル、Ｃ_１－６ハロアルキル、Ｃ_３－８シクロアルキル、－Ｃ_１－６アルキル－Ｃ_３－８シクロアルキル、フェニル、－Ｃ_１－６アルキル－フェニル、Ｃ_２－９ヘテロシクロアルキル、－Ｃ_１－６アルキル－Ｃ_２－９ヘテロシクロアルキル、Ｃ_２－９ヘテロアリール、および－Ｃ_１－６アルキル－Ｃ_２－９ヘテロアリールから選択され、ここで、Ｃ_１－６アルキル、フェニル、－Ｃ_１－６アルキル－フェニル、－Ｃ_１－６アルキル－Ｃ_２－９ヘテロシクロアルキル、Ｃ_２－９ヘテロアリール、および－Ｃ_１－６アルキル－Ｃ_２－９ヘテロアリールは、Ｃ_１－６アルキル、－ＯＲ１１、－Ｎ（Ｒ^１１）_２、Ｃ_１－６アルキル、Ｃ_３－８シクロアルキル、－Ｃ（Ｏ）Ｒ^１２、および－Ｃ（Ｏ）ＯＲ^１２から独立して選択される１つまたは２つの基で随意に置換され；
Ｒ^１０はそれぞれ独立して、Ｈ、Ｃ_１－６アルキル、Ｃ_１－６ハロアルキル、Ｃ_３－８シクロアルキル、－Ｃ_１－６アルキル－Ｃ_３－８シクロアルキル、フェニル、－Ｃ_１－６アルキル－フェニル、およびＣ_２－９ヘテロアリールから選択され、ここで、Ｃ_１－６アルキル、フェニル、－Ｃ_１－６アルキル－フェニル、およびＣ_２－９ヘテロアリールは、ハロゲン、Ｃ_１－６アルキル、－Ｎ（Ｒ^１１）_２、および－Ｃ（Ｏ）ＯＲ^１２から独立して選択される１つまたは２つの基で随意に置換され；あるいは、２つのＲ^１０、およびそれらが結合している窒素原子は一緒になって、Ｃ_１－６アルキル、オキソ、および－Ｃ（Ｏ）ＯＨから独立して選択される１つ、２つ、または３つの基で随意に置換された５員または６員のヘテロシクロアルキル環を形成し；
Ｒ^１１はそれぞれ独立して、ＨおよびＣ_１－６アルキルから選択され；
Ｒ^１２は独立して、ＨおよびＣ_１－６アルキルから選択され；
ｎは、０、１、２、または３であり；
ｐは、０、１、２、３、４、または５であり；
ｑは、０、１、２、３、または４である。

And;
^R7 is independently selected from H and C _1-6 alkyl;
R ⁸ are independently halogen, -OH, -OR ⁹ , -N (R ¹⁰ ) ₂ , -S (O) R ⁹ , -S (O) ₂ R ⁹ , -NHS (O) ₂ R ⁹ , -S (O) ₂ N (R ¹⁰ ) ₂ , -C (O) NHS (O) ₂ N (R ¹⁰ ) ₂ , -C (O) R ⁹ , -C (O) OR ¹⁰ , -OC ( O) R ⁹ , -C (O) N (R ¹⁰ ) ₂ , -OC (O) N (R ¹⁰ ) ₂ , -NR ¹⁰ C (O) N (R ¹⁰ ) ₂ , -NR ¹⁰ C (O) R ⁹ , -NR ¹⁰ C (O) OR ⁹ , C _1-6 alkyl, -C _1-6 alkyl-OH, -C _1-6 alkyl-OR ⁹ , -C _1-6 alkyl-N (R ¹⁰ ) ₂ , -C _1-6 alkyl-C (O) OR ¹⁰ , C _1-6 haloalkyl, C _1-6 haloalkyl-OH, C _3-8 cycloalkyl, -C _1-6 alkyl-C _3-8 cycloalkyl , Phenyl, -C _1-6 alkyl-phenyl, C _2-9 heterocycloalkyl, and C _1-9 heteroaryl; where phenyl, -C _1-6 alkyl-phenyl, and C _1-9 Heteroaryl is one, two or three groups independently selected from halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, and C _2-9 heterocycloalkyl. And where C _2-9 heterocycloalkyl is selected independently of halogen, C _1-6 alkyl, C _1-6 haloalkyl, and oxo, one, two, or three. Arbitrarily replaced by one group;
R ⁹ are independently C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, -C _1-6 alkyl-C _3-8 cycloalkyl, phenyl, -C _1-6 alkyl- Selected from phenyl, C _2-9 heterocycloalkyl, -C _1-6 alkyl-C _2-9 heterocycloalkyl, C _2-9 heteroaryl, and -C _1-6 alkyl-C _2-9 heteroaryl, Here, C _1-6 alkyl, phenyl, -C _1-6 alkyl-phenyl, -C _1-6 alkyl-C _2-9 heterocycloalkyl, C _2-9 heteroaryl, and -C _1-6 alkyl- C _2-9 heteroaryls are C _1-6 alkyl, -OR 11, -N (R ¹¹ ) ₂ , C _1-6 alkyl, C _3-8 cycloalkyl, -C (O) R ¹² , and -C ( O) Optionally substituted with one or two groups independently selected from OR ¹² ;
R ¹⁰ are independently H, C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, -C _1-6 alkyl-C _3-8 cycloalkyl, phenyl, -C _1-6 . Selected from alkyl-phenyl and C _2-9 heteroaryl, where C _1-6 alkyl, phenyl, -C _1-6 alkyl-phenyl, and C _2-9 heteroaryl are halogen, C _1-6 . It is optionally substituted with one or two groups independently selected from alkyl, -N (R ¹¹ ) ₂ , and -C (O) OR ¹² ; or two R ^10s , and they are combined. The nitrogen atoms present together are 5-membered or optionally substituted with one, two, or three groups independently selected from C _1-6 alkyl, oxo, and -C (O) OH. Forming a 6-membered heterocycloalkyl ring;
R ¹¹ is independently selected from H and C _1-6 alkyl;
^R12 is independently selected from H and C _1-6 alkyl;
n is 0, 1, 2, or 3;
p is 0, 1, 2, 3, 4, or 5;
q is 0, 1, 2, 3, or 4.

In some embodiments, there are compounds of formula (I), (I'), or (I''), or pharmaceutically acceptable salts or solvates thereof, wherein R ¹ is:

である。いくつかの実施形態では、式（Ｉ）、（Ｉ’）、または（Ｉ’’）の化合物、またはそれらの薬学的に許容可能な塩あるいは溶媒和物があり、ここで、ｐは、０、１、または２である。いくつかの実施形態では、式（Ｉ）、（Ｉ’）、または（Ｉ’’）の化合物、またはそれらの薬学的に許容可能な塩あるいは溶媒和物があり、ここで、Ｒ^５はそれぞれ独立して、ハロゲン、－ＯＨ、－ＯＲ^９、－Ｎ（Ｒ^１０）_２、－Ｓ（Ｏ）_２Ｒ^９、－ＮＨＳ（Ｏ）_２Ｒ^９、－Ｓ（Ｏ）_２Ｎ（Ｒ^１０）_２、－Ｃ（Ｏ）ＮＨＳ（Ｏ）_２Ｎ（Ｒ^１０）_２、－Ｃ（Ｏ）Ｒ^９、－Ｃ（Ｏ）ＯＲ^１０、－ＯＣ（Ｏ）Ｒ^９、－Ｃ（Ｏ）Ｎ（Ｒ^１０）_２、－ＯＣ（Ｏ）Ｎ（Ｒ^１０）_２、－ＮＲ^１０Ｃ（Ｏ）Ｎ（Ｒ^１０）_２、－ＮＲ^１０Ｃ（Ｏ）Ｒ^９、Ｃ_１－６アルキル、－Ｃ_１－６アルキル－ＯＨ、－Ｃ_１－６アルキル－ＯＲ^９、－Ｃ_１－６アルキル－Ｎ（Ｒ^１０）_２、－Ｃ_１－６アルキル－Ｃ（Ｏ）ＯＲ^１０、Ｃ_１－６ハロアルキル、Ｃ_１－６ハロアルキル－ＯＨ、Ｃ_３－８シクロアルキル、Ｃ_２－９ヘテロシクロアルキル、およびＣ_１－９ヘテロアリールから選択される。いくつかの実施形態では、式（Ｉ）、（Ｉ’）、または（Ｉ’’）の化合物、またはそれらの薬学的に許容可能な塩あるいは溶媒和物があり、ここで、Ｒ^５はそれぞれ独立して、ハロゲン、－ＯＨ、－ＯＲ^９、－Ｎ（Ｒ^１０）_２、－Ｃ（Ｏ）ＮＨＳ（Ｏ）_２Ｎ（Ｒ^１０）_２、－Ｃ（Ｏ）ＯＲ^１０、－Ｃ（Ｏ）Ｎ（Ｒ^１０）_２、－ＮＲ^１０Ｃ（Ｏ）Ｒ^９、Ｃ_１－６アルキル、－Ｃ_１－６アルキル－Ｃ（Ｏ）ＯＲ^１０、およびＣ_１－９ヘテロアリールから選択される。いくつかの実施形態では、式（Ｉ）、（Ｉ’）、または（Ｉ’’）の化合物、またはそれらの薬学的に許容可能な塩あるいは溶媒和物があり、ここで、Ｒ^５はそれぞれ独立して、－ＯＲ^９、－Ｃ（Ｏ）ＯＲ^１０、－Ｃ（Ｏ）Ｎ（Ｒ^１０）_２、Ｃ_１－６アルキル、－Ｃ_１－６アルキル－Ｃ（Ｏ）ＯＲ^１０、および、

Is. In some embodiments, there are compounds of formula (I), (I'), or (I''), or pharmaceutically acceptable salts or solvates thereof, where p is 0. 1, or 2. In some embodiments, there are compounds of formula (I), (I'), or (I''), or pharmaceutically acceptable salts or admixtures thereof, wherein R ⁵ is each. Independently, halogen, -OH, -OR ⁹ , -N (R ¹⁰ ) ₂ , -S (O) ₂ R ⁹ , -NHS (O) ₂ R ⁹ , -S (O) ₂ N (R ¹⁰ ) ₂ , -C (O) NHS (O) ₂ N (R ¹⁰ ) ₂ , -C (O) R ⁹ , -C (O) OR ¹⁰ , -OC (O) R ⁹ , -C (O) N ( R ¹⁰ ) ₂ , -OC (O) N (R ¹⁰ ) ₂ , -NR ¹⁰ C (O) N (R ¹⁰ ) ₂ , -NR ¹⁰ C (O) R ⁹ , C _1-6 alkyl, -C _{1 -6} alkyl-OH, -C _1-6 alkyl-OR ⁹ , -C _1-6 alkyl-N (R ¹⁰ ) ₂ , -C _1-6 alkyl-C (O) OR ¹⁰ , C _1-6 haloalkyl, It is selected from C _1-6 haloalkyl-OH, C _3-8 cycloalkyl, C _2-9 heterocycloalkyl, and C _1-9 heteroaryl. In some embodiments, there are compounds of formula (I), (I'), or (I''), or pharmaceutically acceptable salts or solvates thereof, wherein R ⁵ is each. Independently, halogen, -OH, -OR ⁹ , -N (R ¹⁰ ) ₂ , -C (O) NHS (O) ₂ N (R ¹⁰ ) ₂ , -C (O) OR ¹⁰ , -C (O) ) N (R ¹⁰ ) ₂ , -NR ¹⁰ C (O) R ⁹ , C _1-6 alkyl, -C _1-6 alkyl-C (O) OR ¹⁰ , and C _1-9 heteroaryl. In some embodiments, there are compounds of formula (I), (I'), or ⁽ I''), or pharmaceutically acceptable salts or solvates thereof, wherein R5 is each. Independently, -OR ⁹ , -C (O) OR ¹⁰ , -C (O) N (R ¹⁰ ) ₂ , C _1-6 alkyl, -C _1-6 alkyl-C (O) OR ¹⁰ , and

から選択されるいくつかの実施形態では、式（Ｉ）、（Ｉ’）、または（Ｉ’’）の化合物、またはそれらの薬学的に許容可能な塩あるいは溶媒和物があり、ここで、Ｒ^５はそれぞれ独立して、－Ｃ（Ｏ）ＯＲ^１０から選択される。いくつかの実施形態では、式（Ｉ）、（Ｉ’）、または（Ｉ’’）の化合物、またはそれらの薬学的に許容可能な塩あるいは溶媒和物があり、ここで、Ｒ^５はそれぞれ独立して、－ＯＨ、－ＯＲ^９、および－Ｃ_１－６アルキル－Ｃ（Ｏ）ＯＲ^１０から選択される。いくつかの実施形態では、式（Ｉ）、（Ｉ’）、または（Ｉ’’）の化合物、またはそれらの薬学的に許容可能な塩あるいは溶媒和物があり、ここで、Ｒ^９は、－Ｃ（Ｏ）ＯＲ^１２で随意に置換されたＣ_１－６アルキルである。いくつかの実施形態では、式（Ｉ）、（Ｉ’）、または（Ｉ’’）の化合物、またはそれらの薬学的に許容可能な塩あるいは溶媒和物があり、ここで、Ｒ^１０はそれぞれ独立して、ＨおよびＣ_１－６アルキルから選択される。いくつかの実施形態では、式（Ｉ）、（Ｉ’）、または（Ｉ’’）の化合物、またはそれらの薬学的に許容可能な塩あるいは溶媒和物があり、ここで、ｐは１または２である。いくつかの実施形態では、式（Ｉ）、（Ｉ’）、または（Ｉ’’）の化合物、またはそれらの薬学的に許容可能な塩あるいは溶媒和物があり、ここで、ｐは１である。いくつかの実施形態では、式（Ｉ）、（Ｉ’）、または（Ｉ’’）の化合物、またはそれらの薬学的に許容可能な塩あるいは溶媒和物があり、ここで、ｐは２である。いくつかの実施形態では、式（Ｉ）、（Ｉ’）、または（Ｉ’’）の化合物、またはそれらの薬学的に許容可能な塩あるいは溶媒和物があり、ここで、ｐは０である。いくつかの実施形態では、式（Ｉ）、（Ｉ’）、または（Ｉ’’）の化合物、またはそれらの薬学的に許容可能な塩あるいは溶媒和物があり、ここで、Ｒ^１は、１つ、２つ、または３つのＲ^８基で随意に置換された５員または６員のヘテロアリールである。いくつかの実施形態では、式（Ｉ）、（Ｉ’）、または（Ｉ’’）の化合物、またはそれらの薬学的に許容可能な塩あるいは溶媒和物があり、ここで、Ｒ^１は、１つ、２つ、または３つのＲ^８基で随意に置換された５員のヘテロアリールである。いくつかの実施形態では、式（Ｉ）、（Ｉ’）、または（Ｉ’’）の化合物、またはそれらの薬学的に許容可能な塩あるいは溶媒和物があり、ここで、Ｒ^１は、１つ、２つ、または３つのＲ^８基で随意に置換された５員のヘテロアリールであり、ここで、５員のヘテロアリールは、オキサゾリル、チアゾリル、ピラゾリル、フラニル、チエニル、ピロリル、イミダゾリル、トリアゾリル、テトラゾリル、イソキサゾリル、イソチアゾリル、オキサジアゾリル、およびチアジアゾリルから選択される。いくつかの実施形態では、式（Ｉ）、（Ｉ’）、または（Ｉ’’）の化合物、またはそれらの薬学的に許容可能な塩あるいは溶媒和物があり、ここで、Ｒ^１は、１つまたは２つのＲ^８基で随意に置換された５員のヘテロアリールであり、ここで、５員のヘテロアリールは、オキサゾリル、チアゾリル、ピラゾリル、フラニル、チエニル、ピロリル、テトラゾリル、およびイソキサゾリルから選択される。いくつかの実施形態では、式（Ｉ）、（Ｉ’）、または（Ｉ’’）の化合物、またはそれらの薬学的に許容可能な塩あるいは溶媒和物があり、ここで、Ｒ^１は、１つ、２つ、または３つのＲ^８基で随意に置換された６員のヘテロアリールである。いくつかの実施形態では、式（Ｉ）、（Ｉ’）、または（Ｉ’’）の化合物、またはそれらの薬学的に許容可能な塩あるいは溶媒和物があり、ここで、Ｒ^１は、１つ、２つ、または３つのＲ^８基で随意に置換された６員のヘテロアリールであり、ここで、６員のヘテロアリールは、ピリジニル、ピリミジニル、ピラジニル、ピリダジニル、およびトリアジニルから選択される。いくつかの実施形態では、式（Ｉ）、（Ｉ’）、または（Ｉ’’）の化合物、またはそれらの薬学的に許容可能な塩あるいは溶媒和物があり、ここで、Ｒ^１は、１つまたは２つのＲ^８基で随意に置換された６員のヘテロアリールであり、ここで、６員のヘテロアリールは、ピリジニルおよびピリミジニルから選択される。いくつかの実施形態では、式（Ｉ）、（Ｉ’）、または（Ｉ’’）の化合物、またはそれらの薬学的に許容可能な塩あるいは溶媒和物があり、ここで、Ｒ^８はそれぞれ独立して、ハロゲン、－Ｃ（Ｏ）ＯＲ^１０、Ｃ_１－６アルキル、および－Ｃ_１－６アルキル－Ｃ（Ｏ）ＯＲ^１０から選択される。いくつかの実施形態では、式（Ｉ）、（Ｉ’）、または（Ｉ’’）の化合物、またはそれらの薬学的に許容可能な塩あるいは溶媒和物があり、Ｒ^８はそれぞれ独立して、－Ｃ（Ｏ）ＯＲ^１０から選択される。いくつかの実施形態では、式（Ｉ）、（Ｉ’）、または（Ｉ’’）の化合物、またはそれらの薬学的に許容可能な塩あるいは溶媒和物があり、ここで、Ｒ^１は、オキサゾリル、チアゾリル、ピラゾリル、フラニル、チエニル、ピロリル、テトラゾリル、およびイソキサゾリルから選択された非置換の５員のヘテロアリールである。いくつかの実施形態では、式（Ｉ）、（Ｉ’）、または（Ｉ’’）の化合物、またはそれらの薬学的に許容可能な塩あるいは溶媒和物があり、ここで、Ｒ^１は、ピリジニルおよびピリミジニルから選択された非置換の６員のヘテロアリールである。いくつかの実施形態では、式（Ｉ）、（Ｉ’）、または（Ｉ’’）の化合物、またはそれらの薬学的に許容可能な塩あるいは溶媒和物があり、ここで、Ｒ^１は－Ｃ（Ｏ）Ｎ（Ｒ^１０）_２である。いくつかの実施形態では、式（Ｉ）、（Ｉ’）、または（Ｉ’’）の化合物、またはそれらの薬学的に許容可能な塩あるいは溶媒和物があり、ここで、Ｒ^１は－Ｎ（Ｒ^１０）_２である。いくつかの実施形態では、式（Ｉ）、（Ｉ’）、または（Ｉ’’）の化合物、またはそれらの薬学的に許容可能な塩あるいは溶媒和物があり、ここで、Ｒ^１０はそれぞれ独立して、Ｈ、Ｃ_１－６アルキル、Ｃ_１－６ハロアルキル、Ｃ_３－８シクロアルキル、－Ｃ_１－６アルキル－Ｃ_３－８シクロアルキル、フェニル、－Ｃ_１－６アルキル－フェニル、およびＣ_２－９ヘテロアリールから選択され、ここで、Ｃ_１－６アルキル、フェニル、－Ｃ_１－６アルキル－フェニル、およびＣ_２－９ヘテロアリールは、ハロゲン、Ｃ_１－６アルキル、－Ｎ（Ｒ^１１）_２、および－Ｃ（Ｏ）ＯＲ^１２から独立して選択された１つまたは２つの基で随意に置換される。いくつかの実施形態では、式（Ｉ）、（Ｉ’）、または（Ｉ’’）の化合物、またはそれらの薬学的に許容可能な塩あるいは溶媒和物があり、ここで、Ｒ^１０はそれぞれ独立して、Ｈ、Ｃ_１－６アルキル、Ｃ_３－８シクロアルキル、フェニル、およびＣ_２－９ヘテロアリールから選択され、ここで、Ｃ_１－６アルキル、フェニル、およびＣ_２－９ヘテロアリールは独立して、ハロゲン、Ｃ_１－６アルキル、－Ｎ（Ｒ^１１）_２、および－Ｃ（Ｏ）ＯＲ^１２から選択された１つまたは２つの基で置換される。いくつかの実施形態では、式（Ｉ）、（Ｉ’）、または（Ｉ’’）の化合物、またはそれらの薬学的に許容可能な塩あるいは溶媒和物があり、ここで、Ｒ^１０はそれぞれ独立して、Ｈ、および－Ｃ（Ｏ）ＯＲ^１２で随意に置換されたＣ_１－６アルキルから選択される。いくつかの実施形態では、式（Ｉ）、（Ｉ’）、または（Ｉ’’）の化合物、またはそれらの薬学的に許容可能な塩あるいは溶媒和物があり、ここで、２つのＲ^１０、およびそれらが結合する窒素原子は一緒になって、Ｃ_１－６アルキル、オキソ、および－Ｃ（Ｏ）ＯＨから独立して選択された１つ、２つ、または３つの基で随意に置換された５員または６員のヘテロシクロアルキル環を形成する。いくつかの実施形態では、式（Ｉ）、（Ｉ’）、または（Ｉ’’）の化合物、またはそれらの薬学的に許容可能な塩あるいは溶媒和物があり、ここで、２つのＲ^１０、およびそれらが結合する窒素原子は一緒になって、－Ｃ（Ｏ）ＯＨで置換された５員のヘテロシクロアルキル環を形成する。いくつかの実施形態では、式（Ｉ）、（Ｉ’）、または（Ｉ’’）の化合物、またはそれらの薬学的に許容可能な塩あるいは溶媒和物があり、ここで、２つのＲ^１０、およびそれらが結合する窒素原子は一緒になって、－Ｃ（Ｏ）ＯＨで置換された６員のヘテロシクロアルキル環を形成する。いくつかの実施形態では、式（Ｉ）、（Ｉ’）、または（Ｉ’’）の化合物、またはそれらの薬学的に許容可能な塩あるいは溶媒和物があり、ここで、Ｒ^１は－Ｃ（Ｏ）ＯＨである。いくつかの実施形態では、式（Ｉ）、（Ｉ’）、または（Ｉ’’）の化合物、またはそれらの薬学的に許容可能な塩あるいは溶媒和物があり、ここで、Ｒ^１は

In some embodiments selected from, there are compounds of formula (I), (I'), or (I''), or pharmaceutically acceptable salts or solvates thereof, wherein. Each of R ⁵ is independently selected from −C (O) OR ¹⁰ . In some embodiments, there are compounds of formula (I), (I'), or ⁽ I''), or pharmaceutically acceptable salts or solvates thereof, wherein R5 is each. Independently selected from -OH, -OR ⁹ and -C _1-6 alkyl-C (O) OR ¹⁰ . In some embodiments, there are compounds of formula (I), (I'), or (I''), or pharmaceutically acceptable salts or solvates thereof, wherein R ⁹ is: -C _1-6 alkyl optionally substituted with C (O) OR ¹² . In some embodiments, there are compounds of formula (I), (I'), or (I''), or pharmaceutically acceptable salts or solvates thereof, wherein R ¹⁰ is each. Independently selected from H and C _1-6 alkyl. In some embodiments, there are compounds of formula (I), (I'), or (I''), or pharmaceutically acceptable salts or solvates thereof, wherein p is 1 or It is 2. In some embodiments, there are compounds of formula (I), (I'), or (I''), or pharmaceutically acceptable salts or solvates thereof, wherein p is 1. be. In some embodiments, there are compounds of formula (I), (I'), or (I''), or pharmaceutically acceptable salts or solvates thereof, wherein p is 2. be. In some embodiments, there are compounds of formula (I), (I'), or (I''), or pharmaceutically acceptable salts or solvates thereof, where p is 0. be. In some embodiments, there are compounds of formula (I), (I'), or (I''), or pharmaceutically acceptable salts or solvates thereof, wherein R ¹ is: It is a 5- or ⁶ -membered heteroaryl optionally substituted with one, two, or three R8 groups. In some embodiments, there are compounds of formula (I), (I'), or (I''), or pharmaceutically acceptable salts or solvates thereof, wherein R ¹ is: It is a ⁵ -membered heteroaryl optionally substituted with one, two, or three R8 groups. In some embodiments, there are compounds of formula (I), (I'), or (I''), or pharmaceutically acceptable salts or solvates thereof, wherein R ¹ is: A ⁵ -membered heteroaryl optionally substituted with one, two, or three R8 groups, wherein the five-membered heteroaryl is oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, imidazolyl, It is selected from triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, and thiadiazolyl. In some embodiments, there are compounds of formula (I), (I'), or (I''), or pharmaceutically acceptable salts or solvates thereof, wherein R ¹ is: A 5-membered heteroaryl optionally substituted with one or two R8 groups, wherein the ⁵ -membered heteroaryl is selected from oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, tetrazolyl, and isoxazolyl. Will be done. In some embodiments, there are compounds of formula (I), (I'), or (I''), or pharmaceutically acceptable salts or solvates thereof, wherein R ¹ is: It is a ⁶ -membered heteroaryl optionally substituted with one, two, or three R8 groups. In some embodiments, there are compounds of formula (I), (I'), or (I''), or pharmaceutically acceptable salts or solvates thereof, wherein R ¹ is: A 6-membered heteroaryl optionally substituted with one, two, or three R8 groups, wherein the ⁶ -membered heteroaryl is selected from pyridinyl, pyrimidinyl, pyrazinyl, pyridadinyl, and triazinyl. .. In some embodiments, there are compounds of formula (I), (I'), or (I''), or pharmaceutically acceptable salts or solvates thereof, wherein R ¹ is: A 6-membered heteroaryl optionally substituted with one or two R8 groups, wherein the ⁶ -membered heteroaryl is selected from pyridinyl and pyrimidinyl. In some embodiments, there are compounds of formula (I), (I'), or (I''), or pharmaceutically acceptable salts or solvates thereof, wherein R ⁸ is each. Independently selected from halogen, -C (O) OR ¹⁰ , C _1-6 alkyl, and -C _1-6 alkyl-C (O) OR ¹⁰ . In some embodiments, there are compounds of formula (I), (I'), or ⁽ I''), or pharmaceutically acceptable salts or solvates thereof, each of which is independent of R8. , -C (O) OR ¹⁰ is selected. In some embodiments, there are compounds of formula (I), (I'), or (I''), or pharmaceutically acceptable salts or solvates thereof, wherein R ¹ is: It is an unsubstituted 5-membered heteroaryl selected from oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, tetrazolyl, and isoxazolyl. In some embodiments, there are compounds of formula (I), (I'), or (I''), or pharmaceutically acceptable salts or solvates thereof, wherein R ¹ is: It is an unsubstituted 6-membered heteroaryl selected from pyridinyl and pyrimidinyl. In some embodiments, there are compounds of formula (I), (I'), or (I''), or pharmaceutically acceptable salts or solvates thereof, wherein R ¹ is-. C (O) N (R ¹⁰ ) ₂ . In some embodiments, there are compounds of formula (I), (I'), or (I''), or pharmaceutically acceptable salts or solvates thereof, wherein R ¹ is-. N (R ¹⁰ ) ₂ . In some embodiments, there are compounds of formula (I), (I'), or (I''), or pharmaceutically acceptable salts or admixtures thereof, wherein R ¹⁰ is each. Independently, H, C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, -C _1-6 alkyl-C _3-8 cycloalkyl, phenyl, -C _1-6 alkyl-phenyl, And C _2-9 heteroaryl, where C _1-6 alkyl, phenyl, -C _1-6 alkyl-phenyl, and C _2-9 heteroaryl are halogen, C _1-6 alkyl, -N. It is optionally substituted with one or two groups independently selected from (R ¹¹ ) ₂ and -C (O) OR ¹² . In some embodiments, there are compounds of formula (I), (I'), or (I''), or pharmaceutically acceptable salts or admixtures thereof, wherein R ¹⁰ is each. Independently selected from H, C _1-6 alkyl, C _3-8 cycloalkyl, phenyl, and C _2-9 heteroaryl, where C _1-6 alkyl, phenyl, and C _2-9 heteroaryl Is independently substituted with one or two groups selected from halogen, C _1-6 alkyl, -N (R ¹¹ ) ₂ , and -C (O) OR ¹² . In some embodiments, there are compounds of formula (I), (I'), or (I''), or pharmaceutically acceptable salts or solvates thereof, wherein R ¹⁰ is each. Independently selected from H, and C _1-6 alkyl optionally substituted with -C (O) OR ¹² . In some embodiments, there are compounds of formula (I), (I'), or (I''), or pharmaceutically acceptable salts or solvates thereof, wherein the two ^R10s . , And the nitrogen atoms to which they are attached are combined and optionally substituted with one, two, or three groups independently selected from C _1-6 alkyl, oxo, and -C (O) OH. Form a 5- or 6-membered heterocycloalkyl ring. In some embodiments, there are compounds of formula (I), (I'), or (I''), or pharmaceutically acceptable salts or solvates thereof, wherein the two ^R10s . , And the nitrogen atoms to which they bind together form a 5-membered heterocycloalkyl ring substituted with —C (O) OH. In some embodiments, there are compounds of formula (I), (I'), or (I''), or pharmaceutically acceptable salts or solvates thereof, wherein the two ^R10s . , And the nitrogen atoms to which they bind together form a 6-membered heterocycloalkyl ring substituted with —C (O) OH. In some embodiments, there are compounds of formula (I), (I'), or (I''), or pharmaceutically acceptable salts or solvates thereof, wherein R ¹ is-. It is C (O) OH. In some embodiments, there are compounds of formula (I), (I'), or (I''), or pharmaceutically acceptable salts or solvates thereof, wherein R ¹ is.

である。いくつかの実施形態では、式（Ｉ）、（Ｉ’）、または（Ｉ’’）の化合物、またはそれらの薬学的に許容可能な塩あるいは溶媒和物があり、ここで、Ｒ^２は、Ｈ、－ＯＨ、－Ｎ（Ｒ^１０）_２、または－Ｏ－Ｃ_１－６アルキルである。いくつかの実施形態では、式（Ｉ）、（Ｉ’）、または（Ｉ’’）の化合物、またはそれらの薬学的に許容可能な塩あるいは溶媒和物があり、ここで、Ｒ^２は－Ｏ－Ｃ_１－６アルキルである。いくつかの実施形態では、式（Ｉ）、（Ｉ’）、または（Ｉ’’）の化合物、またはそれらの薬学的に許容可能な塩あるいは溶媒和物があり、ここで、Ｒ^２は－ＯＣＨ_２ＣＨ_３である。いくつかの実施形態では、式（Ｉ）、（Ｉ’）、または（Ｉ’’）の化合物、またはそれらの薬学的に許容可能な塩あるいは溶媒和物があり、ここで、Ｒ^２はＨである。いくつかの実施形態では、式（Ｉ）、（Ｉ’）、または（Ｉ’’）の化合物、またはそれらの薬学的に許容可能な塩あるいは溶媒和物があり、ここで、ｎは１である。いくつかの実施形態では、式（Ｉ）、（Ｉ’）、または（Ｉ’’）の化合物、またはそれらの薬学的に許容可能な塩あるいは溶媒和物があり、ここで、Ｒ^３はそれぞれ独立して、ハロゲン、－ＯＨ、－ＯＲ^９、－Ｎ（Ｒ^１０）_２、Ｃ_１－６アルキル、－Ｃ_１－６アルキル－ＯＨ、－Ｃ_１－６アルキル－ＯＲ^９、およびＣ_１－６ハロアルキルから選択される。いくつかの実施形態では、式（Ｉ）、（Ｉ’）、または（Ｉ’’）の化合物、またはそれらの薬学的に許容可能な塩あるいは溶媒和物があり、ここで、Ｒ^３はそれぞれ独立して、ハロゲン、－ＯＲ^９、およびＣ_１－６アルキルから選択される。いくつかの実施形態では、式（Ｉ）、（Ｉ’）、または（Ｉ’’）の化合物、またはそれらの薬学的に許容可能な塩あるいは溶媒和物があり、ここで、Ｒ^３はそれぞれ－ＯＲ^９であり、Ｒ^９はＣ_３－８シクロアルキルである。いくつかの実施形態では、式（Ｉ）、（Ｉ’）、または（Ｉ’’）の化合物、またはそれらの薬学的に許容可能な塩あるいは溶媒和物があり、ここで、ｎは０である。

Is. In some embodiments, there are compounds of formula (I), (I'), or (I''), or pharmaceutically acceptable salts or solvates thereof, wherein R ² is. H, -OH, -N (R ¹⁰ ) ₂ , or -OC _1-6 alkyl. In some embodiments, there are compounds of formula (I), (I'), or (I''), or pharmaceutically acceptable salts or solvates thereof, wherein R ² is-. OC _1-6 alkyl. In some embodiments, there are compounds of formula (I), (I'), or (I''), or pharmaceutically acceptable salts or solvates thereof, wherein R ² is-. OCH ₂ CH ₃ . In some embodiments, there are compounds of formula (I), (I'), or (I''), or pharmaceutically acceptable salts or solvates thereof, wherein R ² is H. Is. In some embodiments, there are compounds of formula (I), (I'), or (I''), or pharmaceutically acceptable salts or solvates thereof, where n is 1. be. In some embodiments, there are compounds of formula (I), (I'), or (I''), or pharmaceutically acceptable salts or solvates thereof, wherein R ³ is each. Independently, halogen, -OH, -OR ⁹ , -N (R ¹⁰ ) ₂ , C _1-6 alkyl, -C _1-6 alkyl-OH, -C _1-6 alkyl-OR ⁹ , and C _{1- 6} Selected from haloalkyl. In some embodiments, there are compounds of formula (I), (I'), or (I''), or pharmaceutically acceptable salts or solvates thereof, wherein R ³ is each. Independently selected from halogen, -OR ⁹ and C _1-6 alkyl. In some embodiments, there are compounds of formula (I), (I'), or (I''), or pharmaceutically acceptable salts or solvates thereof, wherein R ³ is each. -OR ⁹ and R ⁹ is C _3-8 cycloalkyl. In some embodiments, there are compounds of formula (I), (I'), or (I''), or pharmaceutically acceptable salts or solvates thereof, where n is 0. be.

In another embodiment, it comprises a compound of formula (I), (I'), or (I''), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient. Pharmaceutical compositions are described herein.

In another embodiment, there is a method of treating an inflammatory bowel disease in a patient, wherein the method is a therapeutically effective amount of a compound of formula (I), (I'), or (I''), or a pharmaceutical product thereof. Includes the step of administering to the patient a pharmaceutically acceptable salt or solvate. In some embodiments, there is a method of treating inflammatory bowel disease in a patient, wherein the method is a therapeutically effective amount of a compound of formula (I), (I'), or (I''), or The step of administering the pharmaceutically acceptable salt or admixture to the patient, wherein the inflammatory bowel disease includes Crohn's disease, ulcerative bowel disease, and perianal Crohn's disease. Is selected from. In some cases, ulcerative colitis is a severe form of ulcerative colitis. In some cases, the severe form of ulcerative colitis is medically refractory ulcerative colitis.

Another aspect comprises contacting GPR35 or a portion thereof with a compound of formula (I), (I'), or (I''), or a pharmaceutically acceptable salt or solvate thereof. , Methods of regulating GPR35 activity are described herein.

Incorporation by Reference All publications, patents, and patent applications referred to herein are as if the individual publications, patents, or patent applications are specifically and individually indicated to be incorporated by reference. , To the same extent incorporated herein by reference.

Definition

Many terms shall be used in the context of this disclosure.

Unless otherwise specified, the technical and scientific terms used herein have the same meaning as generally understood to which the claimed subject matter belongs. If there are multiple definitions of the terms herein, the definitions in this section will prevail. All patents, patent applications, publications, and published nucleotide and amino acid sequences referenced herein (eg, sequences available in GenBank or other databases) are incorporated by reference. When URLs or other such identifiers or addresses are mentioned, these identifiers can be changed, and certain information on the Internet may appear or disappear, but equivalent information can be found by searching the Internet. Please understand. References to this are evidence of the availability and public dissemination of such information.

It will be appreciated that the general description described above and the detailed description below are merely exemplary and descriptive and do not limit the subject matter of any of the present applications. In this application, the use of the singular includes the plural unless otherwise stated. As used in the specification and the accompanying claims, the singular forms "a", "an", and "the" include multiple references unless the context explicitly specifies otherwise. In this application, the use of "or" means "and / or" unless otherwise stated. Moreover, the use of the term "included", as well as other forms such as "include", "includes", and "included", is not limiting. ..

The paragraph headings used herein are for organizational purposes only and should not be construed as limiting the subject matter described.

Definitions of standard chemistry terms are, but are not limited to, Carey and Sundberg "Advanced Organic Chemistry 4th Ed." Vols. It can be found in references, including A (2000) and B (2001), Plenum Press, New York. Unless otherwise specified, conventional methods of mass spectroscopy, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA technology, and pharmacology.

Unless a specific definition is provided, the nomenclatures adopted in connection with analytical chemistry, synthetic organic chemistry, and medicinal chemistry and medicinal chemistry described herein, and their testing methods and techniques, are the art of the art. It is recognized in. Standard techniques can be used for chemical synthesis, chemical analysis, drug preparation, prescribing, and delivery, as well as patient treatment. Standard techniques can be used for recombinant DNA, oligonucleotide synthesis, and tissue culture and transformation (eg, electroporation, lipofection). Reaction and purification techniques can be performed, for example, using kits from the manufacturer's specifications, or as commonly performed in the technique, or as described herein. The techniques and procedures described above can be performed in generally conventional manners and as described in various general and more specific references cited and discussed throughout this specification.

It will be appreciated that the methods and compositions described herein are not limited to the particular methods, protocols, cell lines, constructs, and reagents described herein and are therefore variable. Moreover, the terms used herein are intended to describe only certain embodiments and are not intended to limit the scope of the methods, compounds, compositions described herein. ..

As used herein, C1-Cx is C1-C2, C1-C3. .. .. Contains C1-Cx. C1-Cx refers to the number of carbon atoms that make up the moiety it specifies (except for any substituents).

The "alkyl" group refers to an aliphatic hydrocarbon group. The alkyl group may or may not contain unsaturated units. The alkyl moiety may be a "saturated alkyl" group, which means that the alkyl moiety does not contain unsaturated units (ie, carbon-carbon double bonds or carbon-carbon triple bonds). The alkyl group may further be an "unsaturated alkyl" moiety, which means that the alkyl group contains at least one unsaturated unit. The alkyl moiety may be branched, linear, or cyclic, saturated or unsaturated.

An "alkyl" group can have 1 to 6 carbon atoms (whenever an alkyl appears herein, a range of numbers such as "1 to 6" refers to each integer in a given range; for example. "1-6 carbon atoms" means that an alkyl group can consist of up to 6 carbon atoms, such as 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., but this definition is a number. Also covers the emergence of the term "alkyl", which does not have a specified range). The alkyl groups of the compounds described herein may be designated as "C1-C _{- 6} alkyl" or a similar name. As just one example, "C1-C6 alkyl" means that there are ₁ to ₆ carbon atoms in the alkyl chain, i.e. the alkyl chain is methyl, ethyl, N-propyl, iso-propyl, N-butyl, Consists of iso-butyl, sec-butyl, T-butyl, N-pentyl, iso-pentyl, neo-pentyl, hexyl, propen-3-yl (allyl), cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl Selected from the group. Alkyl groups may or may not be substituted. The alkyl group can be a monoradical or a diradical (ie, an alkylene group), depending on the structure.

"Alkoxy" refers to the "-O-alkyl" group, where alkyl is as defined herein.

The term "alkenyl" refers to a type of alkyl group in which the first two atoms of the alkyl group form a double bond that is not part of an aromatic group. That is, the alkenyl group starts at atom-C (R) = CR ₂ , where R refers to the rest of the alkenyl group, which may be the same or different. Non-limiting examples of alkenyl groups are -CH = CH ₂ , -C (CH ₃ ) = CH ₂ , -CH = CHCH ₃ , -CH = C (CH ₃ ) ₂ , and -C (CH ₃ ). = CHCH ₃ is mentioned. The alkenyl moiety may be branched, straight or cyclic (in either case, it is also known as a "cycloalkenyl" group). The alkenyl group can have 2 to 6 carbons. The alkenyl group may or may not be substituted. The alkenyl group can be a monoradical or a diradical (ie, an alkenylene group), depending on the structure.

The term "alkynyl" refers to a type of alkyl group in which the first two atoms of the alkyl group form a triple bond. That is, the alkynyl group starts with the atom -C≡CR, where R refers to the rest of the alkynyl group. Non-limiting examples of alkynyl groups include -C≡CH, -C≡CCH ₃ , -C≡CCH ₂ CH ₃ , and -C≡CCH ₂ CH ₂ CH ₃ . The "R" portion of the alkynyl moiety can be branched, straight or cyclic. The alkynyl group can have 2 to 6 carbons. The alkynyl group may or may not be substituted. The alkynyl group can be a monoradical or a diradical (ie, an alkynylene group), depending on the structure.

"Amino" refers to _two -NHs.

The term "alkylamine" or "alkylamino" refers to the -N (alkyl) xHy group, where alkyl is as defined herein, where x and y are x = 1, y =. It is selected from the group of 1 and x = 2, y = 0. When x = 2, the alkyl groups can optionally form a cyclic ring system together with the nitrogen to which they are attached. "Dialkylamino" refers to _two -N (alkyl) groups, where alkyl is as defined herein.

The term "aromatic" refers to a planar ring with a delocalized π-electron system containing 4n + 2π electrons (n is an integer). Aromatic rings can be formed from 5, 6, 7, 8, 9, or 9 or more atoms. Aromatic compounds can be replaced at will. The term "aromatic" includes both aryl groups (eg, phenyl, naphthalenyl) and heteroaryl groups (eg, pyridinyl, quinolinyl).

As used herein, the term "aryl" refers to an aromatic ring in which each of the atoms forming the ring is a carbon atom. Aryl rings can be formed by 5, 6, 7, 8, 9, or 9 or more carbon atoms. Aryl groups can be optionally substituted. Examples of aryl groups include, but are not limited to, phenyl and naphthalenyl. Aryl groups can be monoradicals or diradicals (ie, arylene groups), depending on the structure.

"Carboxy" refers to -CO ₂ H. In some embodiments, the carboxy moiety may be replaced with a "carboxylic acid bioisostere", which exhibits physical and / or chemical properties similar to the carboxylic acid moiety. Refers to a functional group or part. Carboxylic acid bio-distributed electrons have similar biological properties as carboxylic acid groups. A compound containing a carboxylic acid moiety can exchange the carboxylic acid moiety with a carboxylic acid bio-isolated electron compound and has similar physical and / or biological properties as compared to a compound containing a carboxylic acid moiety. obtain. For example, in one embodiment, the carboxylic acid bioisostere will be ionized at physiological pH to about the same extent as the carboxylic acid group. Examples of carboxylic acid bioisosteres include, but are not limited to.

などが挙げられる。

And so on.

The term "cycloalkyl" refers to monocyclic or polycyclic non-aromatic radicals, where each of the atoms forming the ring (ie, the skeletal atom) is a carbon atom. Cycloalkyl can be saturated or partially unsaturated. Cycloalkyl can be condensed with an aromatic ring (in which case cycloalkyl is bonded via a non-aromatic ring carbon atom). Cycloalkyl groups include groups with 3-10 cyclic atoms.

The term "heteroaryl" or alternatively "heteroaromatic" refers to an aryl group containing one or more ring heteroatoms selected from nitrogen, oxygen, and sulfur. The "heteroaromatic" or "heteroaryl" moiety comprising N refers to an aromatic group in which at least one of the skeletal atoms of the ring is a nitrogen atom.

A "heterocycloalkyl" or "heteroalicyclic" group refers to a cycloalkyl group in which at least one skeletal ring atom is a heteroatom selected from nitrogen, oxygen, and sulfur. Radicals may be condensed with aryl or heteroaryl. The term heteroalicyclic also includes, but is not limited to, all cyclic forms of carbohydrates, including monosaccharides, disaccharides, and oligosaccharides. Unless otherwise specified, heterocycloalkyl has 2-10 carbons in the ring. When referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is that of the atoms that make up the heterocycloalkyl (ie, the skeletal atoms of the heterocycloalkyl ring) (including the heteroatoms). Note that it is not the same as the total number.

The term "halo" or alternative "halogen" means fluoro, chloro, bromo, and iodine.

The term "haloalkyl" refers to an alkyl group substituted with one or more halogens. Halogen can be the same or different. Non-limiting examples of haloalkyl include -CH ₂ Cl, -CF ₃ , -CHF ₂ , -CH ₂ CF ₃ , -CF ₂ CF ₃ and the like.

The terms "fluoroalkyl" and "fluoroalkoxy" include alkyl and alkoxy groups substituted with one or more fluorine atoms, respectively. Non-limiting examples of fluoroalkyl include -CF ₃ , -CHF ₂ , -CH ₂ F, -CH ₂ CF ₃ , -CF ₂ CF ₃ , -CF ₂ CF ₂ CF ₃ , -CF (CH ₃ ). ₂ and the like. Non-limiting examples of fluoroalkoxy groups include -OCF ₃ , -OCHF ₂ , -OCH ₂ F, -OCH ₂ CF ₃ , -OCF ₂ CF ₃ , -OCF ₂ CF ₂ CF ₃ , -OCF (CH ₃ ). ) ₂ and the like.

The term "heteroalkyl" refers to an alkyl radical in which one or more skeletal chain atoms are selected from non-carbon atoms such as oxygen, nitrogen, sulfur, phosphorus, silicon, or a combination thereof. Heteroatoms may be located at any internal position of the heteroalkyl group. Examples include, but are not limited to, -CH ₂ -O-CH ₃ , -CH ₂ -CH ₂ -O-CH ₃ , -CH ₂ -NH-CH ₃ , -CH ₂ -CH ₂ -NH-CH ₃ , -CH ₂ -N (CH ₃ ) -CH ₃ , -CH ₂ -CH ₂ -NH-CH ₃ , -CH2-CH ₂ -N (CH ₃ ) -CH ₃ , -CH ₂ -SCH ₂ -CH ₃ , -CH ₂ -CH ₂ -S (O) -CH ₃ , -CH ₂ -CH ₂ -S (O) ₂ -CH ₃ , -CH ₂ -NH-OCH ₃ , -CH ₂ -O-Si ( CH ₃ ) ₃ , -CH ₂ -CH = N-OCH ₃ , and -CH = CH-N (CH ₃ ) -CH ₃ . In addition, up to two heteroatoms may be contiguous, for example, -CH ₂ -NH-OCH ₃ and -CH ₂ -O-Si (CH ₃ ) ₃ . Except for the number of heteroatoms, a "heteroalkyl" may have 1 to 6 carbon atoms.

The term "bond" or "single bond" refers to a chemical bond between two atoms or between two parts where the atoms bonded by the bond are considered to be part of a larger substructure.

The term "part" refers to a particular segment or functional group of a molecule. Chemical moieties are often recognized as chemicals embedded or added to the molecule.

As used herein, the single and unspecified substituent "R" is an alkyl, haloalkyl, heteroalkyl, alkenyl, cycloalkyl, aryl, heteroaryl (bonded via ring carbon). , And a substituent selected from heterocycloalkyl.

"Voluntary" or "voluntarily" means that the event or situation described below may or may not occur, and this description includes examples where the event or situation occurs and cases where it does not occur. Means that.

The term "optionally substituted" or "substituted" means that the referenced group is alkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, -OH, alkoxy, aryloxy, alkylthio, arylthio, Alkyl sulfoxide, aryl sulfoxide, alkyl sulfone, aryl sulfone, -CN, alkin, C ₁ -C ₆ alkyl alkin, halo, acyl, acyloxy, -CO ₂ H, -CO ₂ -alkyl, nitro, haloalkyl, fluoroalkyl, and. One or more additional individually selected from aminos, including mono- and di-substituted amino groups (eg, -NH ₂ , -NHR, -N (R) ₂ ) and protected derivatives thereof. It means that it may be substituted with a group. As an example, the optional substituent may be an ^{L SRS} , where the ^LS are independent, single bond, —O—, —C (= O) −, —S—, —S, respectively. (= O)-, -S (= O) _2- , -NH-, -NHC (O)-, -C (O) NH-, S (= O) ₂ NH-, -NHS (= O) ₂ , -OC (O) NH-, -NHC (O) O-,-(C ₁ -C ₆ alkyl)-, or-(C ₂ -C ₆ alkenyl)-; and ^RS are independent of each other. It is then selected from H, (C1 _- C ₆ alkyl), (C ₃ -C ₈ cycloalkyl), aryl, heteroaryl, heterocycloalkyl, and C1 _- C ₆ heteroalkyl. Protecting groups capable of forming protective derivatives of the above substituents can be found in sources such as Greene and Wuts above.

As used herein, the term "about" or "approximately" means within 20%, preferably within 10%, and more preferably within 5% of a given value or range.

As used herein, the term "therapeutically effective amount" is used to treat at least partially the diseases described herein when administered to a mammal in need. Refers to the amount of a compound of formula (I), (I'), (I''), (Ia), (Ib), (Ic), or (Id) that is valid.

The term "regulate" includes either diminished or increased activity, depending on the target molecule.

The term "activating factor" as used herein refers to whether the molecular species itself binds to the receptor, or whether the metabolite of the molecular species binds to the receptor when the molecular species is administered topically. Used to indicate any molecular species that results in activation of the indicated receptors, whether or not they do. Thus, the activator can be a ligand for the receptor or an activator that is metabolized to the ligand for the receptor, i.e., a metabolite that is formed in the tissue and is the actual ligand.

The term "patient" or "mammal" refers to humans, non-human primates, dogs, cats, cows, sheep, pigs, mice, or other veterinary or experimental mammals. Those skilled in the art recognize that treatments that reduce the severity of a condition in one species of mammal predict the effect of treatment on another species of mammal.

"Pharmaceutically acceptable salts" include both acids and base addition salts. A pharmaceutically acceptable salt of any one of the compounds described herein is intended to include any pharmaceutically appropriate salt form. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

"Pharmaceutically acceptable acid addition salts" refers to salts that retain the biological effects and properties of free bases, these salts are not biologically or otherwise undesirable. , Hydrochloride, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphite and other inorganic acids. Salts formed of organic acids such as aliphatic monocarboxylic and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids. Also included, and for example acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvate, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartrate acid, citric acid, benzoic acid, cinnamic acid, mandel. A salt containing an acid, methanesulfonic acid, ethanesulfonic acid, Ptoluenesulfonic acid, salicylic acid and the like is included. Therefore, typical salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates. , Metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, trifluoroacetate, propionate, caprylate, isobutyrate, oxalate, malonate, amber salt, sverin Acids, sebasinates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, Examples thereof include toluene sulfonate, phenyl acetate, citrate, lactate, malate, tartrate, methane sulfonate and the like. Salts of amino acids such as alginate, gluconate, and galactouronate have also been contemplated (eg, Berge SM et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 66: 1-19 (. 1997)). Acid addition salts of basic compounds are prepared by contacting the free base with a sufficient amount of the desired acid to produce the salt.

"Pharmaceutically acceptable base addition salt" refers to a salt that retains the biological effects and properties of the free acid, which is not biologically or otherwise undesirable. These salts are prepared by adding an inorganic or organic base to the free acid. In some embodiments, the pharmaceutically acceptable base addition salt is formed of a metal or amine such as an alkali, alkaline earth metal, or organic amine. Examples of the salt derived from the inorganic base include, but are not limited to, salts of sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum. Salts derived from organic bases include, but are not limited to, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basics. Ion exchange resins such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, prokine, N. , N-dibenzylethylenediamine, chloroprocine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, N-methylglucamine, glucosamine, methylglucamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resin, etc. Can be mentioned. See Berge et al. Above.

As used herein, "treat" or "treat" or "alleviate" or "remit" are used interchangeably herein. These terms refer to methods for obtaining beneficial or desirable outcomes, including, but not limited to, therapeutic and / or prophylactic effects. "Therapeutic effect" means eradication or remission of the underlying disease being treated. Moreover, the therapeutic effect is achieved by eradication or remission of one or more of the physiological symptoms associated with the underlying disease, such that improvement is observed in the patient, even though the patient is still suffering from the underlying disease. To. In the case of prophylactic effect, the composition is administered to a patient at risk of developing the disease, or a patient in whom one or more of the physiological symptoms of the disease are reported, even if the particular disease has not been diagnosed. Will be done.

As used herein, "medically refractory" or "refractory" refers to the failure of standard procedures to induce remission of the disease, as used herein. .. In some embodiments, the disease includes an inflammatory disease disclosed herein. Non-limiting examples of refractory inflammatory diseases include refractory Crohn's disease and refractory ulcerative colitis (eg, medically refractory UC, or mrUC). Non-limiting examples of standard treatments include glucocorticosteroids, anti-TNFΑ treatment, anti-A4-B7 treatment (vedolizumab), anti-IL 12P40 treatment (ustekinumab), thalidomide, and cytoxin. Can be mentioned.

G protein-coupled receptor 35 (GPR35)
The G protein-coupled receptor 35 (GPR35) is a receptor for kynurenic acid, which is an intermediate in the tryptophan metabolic pathway. GPR35 mediates calcium recruitment and inositol phosphate production. GPR35, and the nucleic acid encoding GPR35, is characterized by NCBI Entrez GENE ID 2859. Studies have shown that GPR35 is associated with inflammatory regulation by either the presence of receptors on the surface of immune-specific cells or agonist activation leading to altered immune responses. Therefore, it is postulated that GPR35, and the nucleic acids encoding GPR35, play a role in the pathophysiology of inflammatory diseases, making GPR35 an attractive therapeutic target for treating inflammatory diseases or inflammatory diseases.

The compound of formula (I), (I'), or (I'') described herein is a GPR35 modulator. In some embodiments, the compounds of formula (I), (I ′), or (I ″) described herein are GPR35 agonists. In some embodiments, the compounds of formula (I), (I ′), or (I ″) described herein are GPR35 inverse agonists. In some embodiments, the compounds of formula (I), (I ′), or (I ″) described herein are GPR35 antagonists. The compounds of formula (I), (I'), or (I'') described herein, and compositions comprising these compounds, are useful in the treatment of inflammatory bowel disease.

In some embodiments, compounds of formula (I ″), or pharmaceutically acceptable salts or solvates thereof, are provided herein.

式中、
Ｒ^１は、－ＣＨ_２Ｒ^４、－ＣＮ、－Ｂ（ＯＨ）_２、－Ｎ（Ｒ^１０）_２、－ＮＲ^１０Ｃ（Ｏ）Ｒ^９、－Ｃ（Ｏ）ＯＨ、－ＣＨ_２Ｃ（Ｏ）ＯＨ、－Ｃ（Ｏ）Ｎ（Ｒ^１０）_２、－Ｃ（Ｏ）ＮＨＳ（Ｏ）_２Ｎ（Ｒ^１０）_２、－Ｃ_１－６アルキル－ＯＨ、Ｃ_３－８シクロアルキル、

During the ceremony
R ¹ is -CH ₂ R ⁴ , -CN, -B (OH) ₂ , -N (R ¹⁰ ) ₂ , -NR ¹⁰ C (O) R ⁹ , -C (O) OH, -CH ₂ C ( O) OH, -C (O) N (R ¹⁰ ) ₂ , -C (O) NHS (O) ₂ N (R ¹⁰ ) ₂ , -C _1-6 alkyl-OH, C _3-8 cycloalkyl,

、または１つ、２つ、あるいは３つのＲ^８基で随意に置換された５員または６員のヘテロアリールであり；
Ｒ^２は、Ｈ、－ＯＨ、－Ｎ（Ｒ^１０）_２、－ＮＨＳ（Ｏ）_２Ｒ^９、－Ｓ（Ｏ）_２Ｎ（Ｒ^１０）_２、－Ｃ（Ｏ）Ｎ（Ｒ^１０）_２、－ＯＣ（Ｏ）Ｎ（Ｒ^１０）_２、－Ｏ－Ｃ_１－６アルキル、－Ｃ_１－６アルキル－ＯＨ、－Ｃ_１－６アルキル－ＯＲ^９、－Ｃ_１－６アルキル－Ｎ（Ｒ^１０）_２、Ｃ_２－６アルケニル、Ｃ_２－６アルキニル、Ｃ_１－６ハロアルキル、Ｃ_３－８シクロアルキルであり；
Ｒ^３はそれぞれ独立して、ハロゲン、－ＣＮ、－ＯＨ、－ＯＲ^９、－ＳＲ^９、－Ｎ（Ｒ^１０）_２、－ＮＯ_２、－Ｓ（Ｏ）Ｒ^９、－Ｓ（Ｏ）_２Ｒ^９、－ＮＨＳ（Ｏ）_２Ｒ^９、－Ｓ（Ｏ）_２Ｎ（Ｒ^１０）_２、－Ｃ（Ｏ）Ｒ^９、－Ｃ（Ｏ）ＯＲ^１０、－ＯＣ（Ｏ）Ｒ^９、－Ｃ（Ｏ）Ｎ（Ｒ^１０）_２、－ＯＣ（Ｏ）Ｎ（Ｒ^１０）_２、－ＮＲ^１０Ｃ（Ｏ）Ｎ（Ｒ^１０）_２、－ＮＲ^１０Ｃ（Ｏ）Ｒ^９、－ＮＲ^１０Ｃ（Ｏ）ＯＲ^９、Ｃ_１－６アルキル、－Ｃ_１－６アルキル－ＯＨ、－Ｃ_１－６アルキル－ＯＲ^９、－Ｃ_１－６アルキル－Ｎ（Ｒ^１０）_２、Ｃ_２－６アルケニル、Ｃ_２－６アルキニル、Ｃ_１－６ハロアルキル、Ｃ_３－８シクロアルキル、および－Ｃ_１－６アルキル－Ｃ_３－８シクロアルキルから選択され；
Ｒ^４は、

, Or a 5- or ⁶ -membered heteroaryl optionally substituted with one, two, or three R8 groups;
R ² is H, -OH, -N (R ¹⁰ ) ₂ , -NHS (O) ₂ R ⁹ , -S (O) ₂ N (R ¹⁰ ) ₂ , -C (O) N (R ¹⁰ ) ₂ , -OC (O) N (R ¹⁰ ) ₂ , -OC _1-6 alkyl, -C _1-6 alkyl-OH, -C _1-6 alkyl-OR ⁹ , -C _1-6 alkyl-N ( R ¹⁰ ) ₂ , C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _3-8 cycloalkyl;
R ³ are independently halogen, -CN, -OH, -OR ⁹ , -SR ⁹ , -N (R ¹⁰ ) ₂ , -NO ₂ , -S (O) R ⁹ , -S (O) ₂ . R ⁹ , -NHS (O) ₂ R ⁹ , -S (O) ₂ N (R ¹⁰ ) ₂ , -C (O) R ⁹ , -C (O) OR ¹⁰ , -OC (O) R ⁹ ,- C (O) N (R ¹⁰ ) ₂ , -OC (O) N (R ¹⁰ ) ₂ , -NR ¹⁰ C (O) N (R ¹⁰ ) ₂ , -NR ¹⁰ C (O) R ⁹ , -NR ¹⁰ C (O) OR ⁹ , C _1-6 alkyl, -C _1-6 alkyl-OH, -C _1-6 alkyl-OR ⁹ , -C _1-6 alkyl-N (R ¹⁰ ) ₂ , C _2-6 Selected from alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, and -C _1-6 alkyl-C _3-8 cycloalkyl;
^R4 is

であり；
Ｒ^５はそれぞれ独立して、ハロゲン、－ＣＮ、－ＯＨ、－ＯＲ^９、－ＳＲ^９、－Ｎ（Ｒ^１０）_２、－Ｓ（Ｏ）Ｒ^９、－Ｓ（Ｏ）_２Ｒ^９、－ＮＨＳ（Ｏ）_２Ｒ^９、－Ｓ（Ｏ）_２Ｎ（Ｒ^１０）_２、－Ｃ（Ｏ）ＮＨＳ（Ｏ）_２Ｎ（Ｒ^１０）_２、－Ｃ（Ｏ）Ｒ^９、－Ｃ（Ｏ）ＯＲ^１０、－ＯＣ（Ｏ）Ｒ^９、－Ｃ（Ｏ）Ｎ（Ｒ^１０）_２、－ＯＣ（Ｏ）Ｎ（Ｒ^１０）_２、－ＮＲ^１０Ｃ（Ｏ）Ｎ（Ｒ^１０）_２、－ＮＲ^１０Ｃ（Ｏ）Ｒ^９、－ＮＲ^１０Ｃ（Ｏ）ＯＲ^９、Ｃ_１－６アルキル、－Ｃ_１－６アルキル－Ｒ^９、－Ｃ_１－６アルキル－ＯＨ、－Ｃ_１－６アルキル－ＯＲ^９、－Ｃ_１－６アルキル－Ｎ（Ｒ^１０）_２、－Ｃ_１－６アルキル－Ｃ（Ｏ）ＯＲ^１０、Ｃ_２－６アルケニル、－Ｃ_２－６アルケニル－Ｃ（Ｏ）ＯＲ^１０、Ｃ_２－６アルキニル、Ｃ_１－６ハロアルキル、Ｃ_１－６ハロアルキル－ＯＨ、Ｃ_３－８シクロアルキル、－Ｃ_１－６アルキル－Ｃ_３－８シクロアルキル、フェニル、－Ｃ_１－６アルキル－フェニル、Ｃ_２－９ヘテロシクロアルキル、－Ｃ_１－６アルキル－Ｃ_２－９ヘテロシクロアルキル、およびＣ_１－９ヘテロアリールから選択され；ここで、Ｃ_３－８シクロアルキル、－Ｃ_１－６アルキル－Ｃ_３－８シクロアルキル、フェニル、－Ｃ_１－６アルキル－フェニル、およびＣ_１－９ヘテロアリールは、ハロゲン、－Ｃ（Ｏ）ＯＲ^１０、Ｃ_１－６アルキル、Ｃ_１－６ハロアルキル、Ｃ_３－８シクロアルキル、およびＣ_２－９ヘテロシクロアルキルから独立して選択される１つ、２つ、または３つの基で随意に置換され；ならびにここで、Ｃ_２－９ヘテロシクロアルキルおよび－Ｃ_１－６アルキル－Ｃ_２－９ヘテロシクロアルキルは、ハロゲン、－Ｃ（Ｏ）ＯＲ^１０、Ｃ_１－６アルキル、Ｃ_１－６ハロアルキル、およびオキソから独立して選択される１つ、２つ、または３つの基で随意に置換され；
Ｒ^６は、－Ｃ（Ｏ）ＯＲ^７、－Ｃ（Ｏ）ＮＨＳ（Ｏ）_２Ｎ（Ｒ^１０）_２、

And;
R ⁵ are independently halogen, -CN, -OH, -OR ⁹ , -SR ⁹ , -N (R ¹⁰ ) ₂ , -S (O) R ⁹ , -S (O) ₂ R ⁹ ,- NHS (O) ₂ R ⁹ , -S (O) ₂ N (R ¹⁰ ) ₂ , -C (O) NHS (O) ₂ N (R ¹⁰ ) ₂ , -C (O) R ⁹ , -C (O) ) OR ¹⁰ , -OC (O) R ⁹ , -C (O) N (R ¹⁰ ) ₂ , -OC (O) N (R ¹⁰ ) ₂ , -NR ¹⁰ C (O) N (R ¹⁰ ) ₂ , -NR ¹⁰ C (O) R ⁹ , -NR ¹⁰ C (O) OR ⁹ , C _1-6 alkyl, -C _1-6 alkyl-R ⁹ , -C _1-6 alkyl-OH, -C _1-6 Alkyl-OR ⁹ , -C _1-6 Alkyl-N (R ¹⁰ ) ₂ , -C _1-6 Alkyl-C (O) OR ¹⁰ , C _2-6 Alkenyl, -C _2-6 Alkenyl-C (O) OR ¹⁰ , C _2-6 alkynyl, C _1-6 haloalkyl, C _1-6 haloalkyl-OH, C _3-8 cycloalkyl, -C _1-6 alkyl-C _3-8 cycloalkyl, phenyl, -C _1- Selected from ₆ Alkyl-Phenyl, C _2-9 Heterocycloalkyl, -C _1-6 Alkyl-C _2-9 Heterocycloalkyl, and C _1-9 Heteroaryl; where C _3-8 Cycloalkyl,- C _1-6 alkyl-C _3-8 cycloalkyl, phenyl, -C _1-6 alkyl-phenyl, and C _1-9 heteroaryl are halogen, -C (O) OR ¹⁰ , C _1-6 alkyl, C. Arbitrarily substituted with one, two, or three groups independently selected from _1-6 haloalkyl, C _3-8 cycloalkyl, and C _2-9 heterocycloalkyl; and where C _{2- 9} Heterocycloalkyl and -C 1-6alkyl-C _2-9 Heterocycloalkyl are selected independently of halogen, -C (O) OR ¹⁰ , C _{1-6 alkyl, C 1-6 haloalkyl} , and oxo. It is optionally replaced with one, two, or three groups;
R ⁶ is -C (O) OR ⁷ , -C (O) NHS (O) ₂ N (R ¹⁰ ) ₂ ,

であり；
Ｒ^７は独立して、ＨおよびＣ_１－６アルキルから選択され；
Ｒ^８はそれぞれ独立して、ハロゲン、－ＯＨ、－ＯＲ^９、－Ｎ（Ｒ^１０）_２、－Ｓ（Ｏ）Ｒ^９、－Ｓ（Ｏ）_２Ｒ^９、－ＮＨＳ（Ｏ）_２Ｒ^９、－Ｓ（Ｏ）_２Ｎ（Ｒ^１０）_２、－Ｃ（Ｏ）ＮＨＳ（Ｏ）_２Ｎ（Ｒ^１０）_２、－Ｃ（Ｏ）Ｒ^９、－Ｃ（Ｏ）ＯＲ^１０、－ＯＣ（Ｏ）Ｒ^９、－Ｃ（Ｏ）Ｎ（Ｒ^１０）_２、－ＯＣ（Ｏ）Ｎ（Ｒ^１０）_２、－ＮＲ^１０Ｃ（Ｏ）Ｎ（Ｒ^１０）_２、－ＮＲ^１０Ｃ（Ｏ）Ｒ^９、－ＮＲ^１０Ｃ（Ｏ）ＯＲ^９、Ｃ_１－６アルキル、－Ｃ_１－６アルキル－ＯＨ、－Ｃ_１－６アルキル－ＯＲ^９、－Ｃ_１－６アルキル－Ｎ（Ｒ^１０）_２、－Ｃ_１－６アルキル－Ｃ（Ｏ）ＯＲ^１０、Ｃ_１－６ハロアルキル、Ｃ_１－６ハロアルキル－ＯＨ、Ｃ_３－８シクロアルキル、－Ｃ_１－６アルキル－Ｃ_３－８シクロアルキル、フェニル、－Ｃ_１－６アルキル－フェニル、Ｃ_２－９ヘテロシクロアルキル、およびＣ_１－９ヘテロアリールから選択され；ここで、フェニル、－Ｃ_１－６アルキル－フェニル、およびＣ_１－９ヘテロアリールは、ハロゲン、Ｃ_１－６アルキル、Ｃ_１－６ハロアルキル、Ｃ_３－８シクロアルキル、およびＣ_２－９ヘテロシクロアルキルから独立して選択される１つ、２つ、または３つの基で随意に置換され；ならびにここで、Ｃ_２－９ヘテロシクロアルキルは、ハロゲン、Ｃ_１－６アルキル、Ｃ_１－６ハロアルキル、およびオキソから独立して選択される１つ、２つ、または３つの基で随意に置換され；
Ｒ^９はそれぞれ独立して、Ｃ_１－６アルキル、Ｃ_１－６ハロアルキル、Ｃ_３－８シクロアルキル、－Ｃ_１－６アルキル－Ｃ_３－８シクロアルキル、フェニル、－Ｃ_１－６アルキル－フェニル、Ｃ_２－９ヘテロシクロアルキル、－Ｃ_１－６アルキル－Ｃ_２－９ヘテロシクロアルキル、Ｃ_２－９ヘテロアリール、および－Ｃ_１－６アルキル－Ｃ_２－９ヘテロアリールから選択され、ここで、Ｃ_１－６アルキル、フェニル、－Ｃ_１－６アルキル－フェニル、－Ｃ_１－６アルキル－Ｃ_２－９ヘテロシクロアルキル、Ｃ_２－９ヘテロアリール、および－Ｃ_１－６アルキル－Ｃ_２－９ヘテロアリールは、Ｃ_１－６アルキル、－ＯＲ１１、－Ｎ（Ｒ^１１）_２、Ｃ_１－６アルキル、Ｃ_３－８シクロアルキル、－Ｎ（Ｒ^１１）Ｃ（Ｏ）Ｒ^１２、－Ｃ（Ｏ）Ｒ^１２、および－Ｃ（Ｏ）ＯＲ^１２から独立して選択される１つまたは２つの基で随意に置換され；
Ｒ^１０はそれぞれ独立して、Ｈ、Ｃ_１－６アルキル、Ｃ_１－６ハロアルキル、Ｃ_３－８シクロアルキル、－Ｃ_１－６アルキル－Ｃ_３－８シクロアルキル、フェニル、－Ｃ_１－６アルキル－フェニル、およびＣ_２－９ヘテロアリールから選択され、ここで、Ｃ_１－６アルキル、フェニル、－Ｃ_１－６アルキル－フェニル、およびＣ_２－９ヘテロアリールは、ハロゲン、Ｃ_１－６アルキル、－Ｎ（Ｒ^１１）_２、および－Ｃ（Ｏ）ＯＲ^１２から独立して選択される１つまたは２つの基で随意に置換され；あるいは、２つのＲ^１０、およびそれらが結合している窒素原子は一緒になって、Ｃ_１－６アルキル、オキソ、および－Ｃ（Ｏ）ＯＨから独立して選択される１つ、２つ、または３つの基で随意に置換された５員または６員のヘテロシクロアルキル環を形成し；
Ｒ^１１はそれぞれ独立して、ＨおよびＣ_１－６アルキルから選択され；
Ｒ^１２はそれぞれ独立して、ＨおよびＣ_１－６アルキルから選択され；
Ｒ^１３はそれぞれ独立して、Ｃ_１－６アルキルから選択され；
ｍは、１、２、３、または４であり；
ｎは、０、１、２、または３であり；
ｐは、０、１、２、３、４、または５であり；および、
ｑは、０、１、２、３、または４である。

And;
^R7 is independently selected from H and C _1-6 alkyl;
R ⁸ are independently halogen, -OH, -OR ⁹ , -N (R ¹⁰ ) ₂ , -S (O) R ⁹ , -S (O) ₂ R ⁹ , -NHS (O) ₂ R ⁹ , -S (O) ₂ N (R ¹⁰ ) ₂ , -C (O) NHS (O) ₂ N (R ¹⁰ ) ₂ , -C (O) R ⁹ , -C (O) OR ¹⁰ , -OC ( O) R ⁹ , -C (O) N (R ¹⁰ ) ₂ , -OC (O) N (R ¹⁰ ) ₂ , -NR ¹⁰ C (O) N (R ¹⁰ ) ₂ , -NR ¹⁰ C (O) R ⁹ , -NR ¹⁰ C (O) OR ⁹ , C _1-6 alkyl, -C _1-6 alkyl-OH, -C _1-6 alkyl-OR ⁹ , -C _1-6 alkyl-N (R ¹⁰ ) ₂ , -C _1-6 alkyl-C (O) OR ¹⁰ , C _1-6 haloalkyl, C _1-6 haloalkyl-OH, C _3-8 cycloalkyl, -C _1-6 alkyl-C _3-8 cycloalkyl , Phenyl, -C _1-6 alkyl-phenyl, C _2-9 heterocycloalkyl, and C _1-9 heteroaryl; where phenyl, -C _1-6 alkyl-phenyl, and C _1-9 Heteroaryl is one, two or three groups independently selected from halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, and C _2-9 heterocycloalkyl. And where C _2-9 heterocycloalkyl is selected independently of halogen, C _1-6 alkyl, C _1-6 haloalkyl, and oxo, one, two, or three. Arbitrarily replaced by one group;
R ⁹ are independently C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, -C _1-6 alkyl-C _3-8 cycloalkyl, phenyl, -C _1-6 alkyl- Selected from phenyl, C _2-9 heterocycloalkyl, -C _1-6 alkyl-C _2-9 heterocycloalkyl, C _2-9 heteroaryl, and -C _1-6 alkyl-C _2-9 heteroaryl, Here, C _1-6 alkyl, phenyl, -C _1-6 alkyl-phenyl, -C _1-6 alkyl-C _2-9 heterocycloalkyl, C _2-9 heteroaryl, and -C _1-6 alkyl- C _2-9 heteroaryls are C _1-6 alkyl, -OR 11, -N (R ¹¹ ) ₂ , C _1-6 alkyl, C _3-8 cycloalkyl, -N (R ¹¹ ) C (O) R ¹² , -C (O) R ¹² , and -C (O) OR ¹² optionally substituted with one or two groups selected independently;
R ¹⁰ are independently H, C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, -C _1-6 alkyl-C _3-8 cycloalkyl, phenyl, -C _1-6 . Selected from alkyl-phenyl and C _2-9 heteroaryl, where C _1-6 alkyl, phenyl, -C _1-6 alkyl-phenyl, and C _2-9 heteroaryl are halogen, C _1-6 . It is optionally substituted with one or two groups independently selected from alkyl, -N (R ¹¹ ) ₂ , and -C (O) OR ¹² ; or two R ^10s , and they are combined. The nitrogen atoms present together are 5-membered or optionally substituted with one, two, or three groups independently selected from C _1-6 alkyl, oxo, and -C (O) OH. Forming a 6-membered heterocycloalkyl ring;
R ¹¹ is independently selected from H and C _1-6 alkyl;
^R12 is independently selected from H and C _1-6 alkyl;
Each R ¹³ is independently selected from C _1-6 alkyl;
m is 1, 2, 3, or 4;
n is 0, 1, 2, or 3;
p is 0, 1, 2, 3, 4, or 5; and
q is 0, 1, 2, 3, or 4.

In some embodiments, there is a compound of formula (I''), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is

である。いくつかの実施形態では、式（Ｉ’’）の化合物、またはその薬学的に許容可能な塩あるいは溶媒和物があり、ここで、Ｒ^１は、

Is. In some embodiments, there is a compound of formula (I''), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is:

であり、ｐは、０、１、または２である。いくつかの実施形態では、式（Ｉ’’）の化合物、またはその薬学的に許容可能な塩あるいは溶媒和物があり、ここで、Ｒ^１は、

And p is 0, 1, or 2. In some embodiments, there is a compound of formula (I''), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is:

であり、ｐは０である。いくつかの実施形態では、式（Ｉ’’）の化合物、またはその薬学的に許容可能な塩あるいは溶媒和物があり、ここで、Ｒ^１は、

And p is 0. In some embodiments, there is a compound of formula (I''), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is:

であり、ｐは１である。いくつかの実施形態では、式（Ｉ’’）の化合物、またはその薬学的に許容可能な塩あるいは溶媒和物があり、ここで、Ｒ^１は、

And p is 1. In some embodiments, there is a compound of formula (I''), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is:

であり、ｐは２である。いくつかの実施形態では、式（Ｉ’’）の化合物、またはその薬学的に許容可能な塩あるいは溶媒和物があり、ここで、Ｒ^１は、

And p is 2. In some embodiments, there is a compound of formula (I''), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is:

であり、ｐは１または２である。いくつかの実施形態では、式（Ｉ’’）の化合物、またはその薬学的に許容可能な塩あるいは溶媒和物があり、ここで、Ｒ^１は、

And p is 1 or 2. In some embodiments, there is a compound of formula (I''), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is:

であり、ｐは１または２であり、Ｒ^５はそれぞれ独立して、ハロゲン、－ＯＨ、－ＯＲ^９、－Ｎ（Ｒ^１０）_２、－Ｓ（Ｏ）_２Ｒ^９、－ＮＨＳ（Ｏ）_２Ｒ^９、－Ｓ（Ｏ）_２Ｎ（Ｒ^１０）_２、－Ｃ（Ｏ）ＮＨＳ（Ｏ）_２Ｎ（Ｒ^１０）_２、－Ｃ（Ｏ）Ｒ^９、－Ｃ（Ｏ）ＯＲ^１０、－ＯＣ（Ｏ）Ｒ^９、－Ｃ（Ｏ）Ｎ（Ｒ^１０）_２、－ＯＣ（Ｏ）Ｎ（Ｒ^１０）_２、－ＮＲ^１０Ｃ（Ｏ）Ｎ（Ｒ^１０）_２、－ＮＲ^１０Ｃ（Ｏ）Ｒ^９、Ｃ_１－６アルキル、－Ｃ_１－６アルキル－ＯＨ、－Ｃ_１－６アルキル－ＯＲ^９、－Ｃ_１－６アルキル－Ｎ（Ｒ^１０）_２、－Ｃ_１－６アルキル－Ｃ（Ｏ）ＯＲ^１０、Ｃ_１－６ハロアルキル、Ｃ_１－６ハロアルキル－ＯＨ、Ｃ_３－８シクロアルキル、Ｃ_２－９ヘテロシクロアルキル、およびＣ_１－９ヘテロアリールから選択される。いくつかの実施形態では、式（Ｉ’’）の化合物、またはその薬学的に許容可能な塩あるいは溶媒和物があり、ここで、Ｒ^１は、

, P is 1 or 2, and R ⁵ is independent of halogen, -OH, -OR ⁹ , -N (R ¹⁰ ) ₂ , -S (O) ₂ R ⁹ , -NHS (O). ₂ R ⁹ , -S (O) ₂ N (R ¹⁰ ) ₂ , -C (O) NHS (O) ₂ N (R ¹⁰ ) ₂ , -C (O) R ⁹ , -C (O) OR ¹⁰ , -OC (O) R ⁹ , -C (O) N (R ¹⁰ ) ₂ , -OC (O) N (R ¹⁰ ) ₂ , -NR ¹⁰ C (O) N (R ¹⁰ ) ₂ , -NR ¹⁰ C (O) R ⁹ , C _1-6 alkyl, -C _1-6 alkyl-OH, -C _1-6 alkyl-OR ⁹ , -C _1-6 alkyl-N (R ¹⁰ ) ₂ , -C _1-6 It is selected from alkyl-C (O) OR ¹⁰ , C _1-6 haloalkyl, C _1-6 haloalkyl-OH, C _3-8 cycloalkyl, C _2-9 heterocycloalkyl, and C _1-9 heteroaryl. In some embodiments, there is a compound of formula (I''), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is:

であり、ｐは１または２であり、Ｒ^５はそれぞれ独立して、ハロゲン、－ＯＨ、－ＯＲ^９、－Ｎ（Ｒ^１０）_２、－Ｓ（Ｏ）_２Ｒ^９、－ＮＨＳ（Ｏ）_２Ｒ^９、－Ｓ（Ｏ）_２Ｎ（Ｒ^１０）_２、－Ｃ（Ｏ）ＮＨＳ（Ｏ）_２Ｎ（Ｒ^１０）_２、－Ｃ（Ｏ）Ｒ^９、－Ｃ（Ｏ）ＯＲ^１０、－ＯＣ（Ｏ）Ｒ^９、－Ｃ（Ｏ）Ｎ（Ｒ^１０）_２、－ＯＣ（Ｏ）Ｎ（Ｒ^１０）_２、－ＮＲ^１０Ｃ（Ｏ）Ｎ（Ｒ^１０）_２、－ＮＲ^１０Ｃ（Ｏ）Ｒ^９、Ｃ_１－６アルキル、－Ｃ_１－６アルキル－ＯＨ、－Ｃ_１－６アルキル－ＯＲ^９、－Ｃ_１－６アルキル－Ｎ（Ｒ^１０）_２、－Ｃ_１－６アルキル－Ｃ（Ｏ）ＯＲ^１０、Ｃ_１－６ハロアルキル、Ｃ_１－６ハロアルキル－ＯＨ、Ｃ_３－８シクロアルキル、Ｃ_２－９ヘテロシクロアルキル、およびＣ_１－９ヘテロアリールから選択され、Ｒ^１０はそれぞれ独立して、ＨおよびＣ_１－６アルキルから選択される。いくつかの実施形態では、式（Ｉ’’）の化合物、またはその薬学的に許容可能な塩あるいは溶媒和物があり、ここで、Ｒ^１は、

, P is 1 or 2, and R ⁵ is independent of halogen, -OH, -OR ⁹ , -N (R ¹⁰ ) ₂ , -S (O) ₂ R ⁹ , -NHS (O). ₂ R ⁹ , -S (O) ₂ N (R ¹⁰ ) ₂ , -C (O) NHS (O) ₂ N (R ¹⁰ ) ₂ , -C (O) R ⁹ , -C (O) OR ¹⁰ , -OC (O) R ⁹ , -C (O) N (R ¹⁰ ) ₂ , -OC (O) N (R ¹⁰ ) ₂ , -NR ¹⁰ C (O) N (R ¹⁰ ) ₂ , -NR ¹⁰ C (O) R ⁹ , C _1-6 alkyl, -C _1-6 alkyl-OH, -C _1-6 alkyl-OR ⁹ , -C _1-6 alkyl-N (R ¹⁰ ) ₂ , -C _1-6 Selected from alkyl-C (O) OR ¹⁰ , C _1-6 haloalkyl, C _1-6 haloalkyl-OH, C _3-8 cycloalkyl, C _2-9 heterocycloalkyl, and C _1-9 heteroaryl, R ¹⁰ are independently selected from H and C _1-6 alkyl. In some embodiments, there is a compound of formula (I''), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is:

であり、ｐは１または２であり、Ｒ^５はそれぞれ独立して、ハロゲン、－ＯＨ、－ＯＲ^９、－Ｎ（Ｒ^１０）_２、－Ｃ（Ｏ）ＮＨＳ（Ｏ）_２Ｎ（Ｒ^１０）_２、－Ｃ（Ｏ）ＯＲ^１０、－Ｃ（Ｏ）Ｎ（Ｒ^１０）_２、－ＮＲ^１０Ｃ（Ｏ）Ｒ^９、Ｃ_１－６アルキル、－Ｃ_１－６アルキル－Ｃ（Ｏ）ＯＲ^１０、およびＣ_１－９ヘテロアリールから選択される。いくつかの実施形態では、式（Ｉ’’）の化合物、またはその薬学的に許容可能な塩あるいは溶媒和物があり、ここで、Ｒ^１は、

, P is 1 or 2, and R ⁵ is independent of halogen, -OH, -OR ⁹ , -N (R ¹⁰ ) ₂ , -C (O) NHS (O) ₂ N (R ¹⁰ ). ) ₂ , -C (O) OR ¹⁰ , -C (O) N (R ¹⁰ ) ₂ , -NR ¹⁰ C (O) R ⁹ , C _1-6 alkyl, -C _1-6 alkyl-C (O) It is selected from OR ¹⁰ and C _1-9 heteroaryl. In some embodiments, there is a compound of formula (I''), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is:

であり、ｐは１または２であり、Ｒ^５はそれぞれ独立して、ハロゲン、－ＯＨ、－ＯＲ^９、－Ｎ（Ｒ^１０）_２、－Ｃ（Ｏ）ＮＨＳ（Ｏ）_２Ｎ（Ｒ^１０）_２、－Ｃ（Ｏ）ＯＲ^１０、－Ｃ（Ｏ）Ｎ（Ｒ^１０）_２、－ＮＲ^１０Ｃ（Ｏ）Ｒ^９、Ｃ_１－６アルキル、－Ｃ_１－６アルキル－Ｃ（Ｏ）ＯＲ^１０、およびＣ_１－９ヘテロアリールから選択され、Ｒ^１０はそれぞれ独立して、ＨおよびＣ_１－６アルキルから選択される。いくつかの実施形態では、式（Ｉ’’）の化合物、またはその薬学的に許容可能な塩あるいは溶媒和物があり、ここで、Ｒ^１は、

, P is 1 or 2, and R ⁵ is independent of halogen, -OH, -OR ⁹ , -N (R ¹⁰ ) ₂ , -C (O) NHS (O) ₂ N (R ¹⁰ ). ) ₂ , -C (O) OR ¹⁰ , -C (O) N (R ¹⁰ ) ₂ , -NR ¹⁰ C (O) R ⁹ , C _1-6 alkyl, -C _1-6 alkyl-C (O) Selected from OR ¹⁰ and C _1-9 heteroaryl, R ¹⁰ is independently selected from H and C _1-6 alkyl, respectively. In some embodiments, there is a compound of formula (I''), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is:

であり、ｐは１または２であり、Ｒ^５はそれぞれ独立して、－ＯＲ^９、－Ｃ（Ｏ）ＯＲ^１０、－Ｃ（Ｏ）Ｎ（Ｒ^１０）_２、Ｃ_１－６アルキル、－Ｃ_１－６アルキル－Ｃ（Ｏ）ＯＲ^１０から選択される。いくつかの実施形態では、式（Ｉ’’）の化合物、またはその薬学的に許容可能な塩あるいは溶媒和物があり、ここで、Ｒ^１は、

, P is 1 or 2, and R ⁵ is independently -OR ⁹ , -C (O) OR ¹⁰ , -C (O) N (R ¹⁰ ) ₂ , C _1-6 alkyl,-, respectively. It is selected from C _1-6 alkyl-C (O) OR ¹⁰ . In some embodiments, there is a compound of formula (I''), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is:

であり、ｐは１または２であり、Ｒ^５はそれぞれ独立して、－ＯＲ^９、－Ｃ（Ｏ）ＯＲ^１０、－Ｃ（Ｏ）Ｎ（Ｒ^１０）_２、Ｃ_１－６アルキル、－Ｃ_１－６アルキル－Ｃ（Ｏ）ＯＲ^１０から選択され、Ｒ^１０はそれぞれ独立して、ＨおよびＣ_１－６アルキルから選択される。いくつかの実施形態では、式（Ｉ’’）の化合物、またはその薬学的に許容可能な塩あるいは溶媒和物があり、ここで、Ｒ^１は、

, P is 1 or 2, and R ⁵ is independently -OR ⁹ , -C (O) OR ¹⁰ , -C (O) N (R ¹⁰ ) ₂ , C _1-6 alkyl,-, respectively. Selected from C _1-6 alkyl-C (O) OR ¹⁰ , R ¹⁰ is independently selected from H and C _1-6 alkyl. In some embodiments, there is a compound of formula (I''), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is:

であり、ｐは１または２であり、Ｒ^５はそれぞれ独立して、－Ｃ（Ｏ）ＯＲ^１０から選択される。いくつかの実施形態では、式（Ｉ’’）の化合物、またはその薬学的に許容可能な塩あるいは溶媒和物があり、ここで、Ｒ^１は、

, P is 1 or 2, and R ⁵ is independently selected from -C (O) OR ¹⁰ . In some embodiments, there is a compound of formula (I''), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is:

であり、ｐは１または２であり、Ｒ^５はそれぞれ独立して、－Ｃ（Ｏ）ＯＲ^１０から選択され、Ｒ^１０はそれぞれ独立して、ＨおよびＣ_１－６アルキルから選択される。いくつかの実施形態では、式（Ｉ’’）の化合物、またはその薬学的に許容可能な塩あるいは溶媒和物があり、ここで、Ｒ^１は、

And p is 1 or 2, R ⁵ is independently selected from -C (O) OR ¹⁰ , and R ¹⁰ is independently selected from H and C _1-6 alkyl. In some embodiments, there is a compound of formula (I''), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is:

であり、ｐは１または２であり、Ｒ^５はそれぞれ独立して、－ＯＨ、－ＯＲ^９、および－Ｃ_１－６アルキル－Ｃ（Ｏ）ＯＲ^１０から選択される。いくつかの実施形態では、式（Ｉ’’）の化合物、またはその薬学的に許容可能な塩あるいは溶媒和物があり、ここで、Ｒ^１は、

, P is 1 or 2, and R ⁵ is independently selected from -OH, -OR ⁹ , and -C _1-6 alkyl-C (O) OR ¹⁰ . In some embodiments, there is a compound of formula (I''), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is:

であり、ｐは１または２であり、Ｒ^５はそれぞれ独立して、－ＯＨ、－ＯＲ^９、および－Ｃ_１－６アルキル－Ｃ（Ｏ）ＯＲ^１０から選択され、Ｒ^９は、－Ｃ（Ｏ）ＯＲ^１２で随意に置換されたＣ_１－６アルキルである。いくつかの実施形態では、式（Ｉ’’）の化合物、またはその薬学的に許容可能な塩あるいは溶媒和物があり、ここで、Ｒ^１は、

And p is 1 or 2, R ⁵ is independently selected from -OH, -OR ⁹ and -C _1-6 alkyl-C (O) OR ¹⁰ , and R ⁹ is -C. (O) C _1-6 alkyl optionally substituted with OR ¹² . In some embodiments, there is a compound of formula (I''), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is:

であり、ｐは１であり、Ｒ^５は独立して、－Ｃ（Ｏ）ＯＨから選択される。

, P is ¹ , and R5 is independently selected from -C (O) OH.

In some embodiments, there is a compound of formula (I''), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is one, two, or three R ^8s . It is a 5- or 6-membered heteroaryl optionally substituted with a group. In some embodiments, there is a compound of formula (I''), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is one, two, or three R ^8s . It is a 5-membered heteroaryl optionally substituted with a group. In some embodiments, there is a compound of formula (I''), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is one, two, or three R ^8s . A 5-membered heteroaryl optionally substituted with a group, wherein the 5-membered heteroaryl is oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, and. Selected from Thiasia Zoril. In some embodiments, there is a compound of formula (I''), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is optionally at one or two R ⁸ groups. Substituted 5-membered heteroaryl, wherein the 5-membered heteroaryl is selected from oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, tetrazolyl, and isoxazolyl. In some embodiments, there is a compound of formula (I''), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is optionally at one or two R ⁸ units. It is a substituted oxazolyl. In some embodiments, there is a compound of formula (I''), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is optionally at one or two R ⁸ units. Substituted thiazolyl. In some embodiments, there is a compound of formula (I''), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is optionally at one or two R ⁸ units. It is a substituted pyrazolyl. In some embodiments, there is a compound of formula (I''), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is optionally at one or two R ⁸ units. It is a substituted flanil. In some embodiments, there is a compound of formula (I''), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is optionally at one or two R ⁸ units. It is a substituted thienyl. In some embodiments, there is a compound of formula (I''), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is optionally at one or two R ⁸ units. It is a substituted pyrrolyl. In some embodiments, there are compounds of formula (I''), or pharmaceutically acceptable salts or solvates thereof, wherein R ¹ is optionally at one or two R ⁸ groups. It is a substituted tetrazolyl. In some embodiments, there is a compound of formula (I''), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is optionally at one or two R ⁸ units. It is a substituted isooxazolyl. In some embodiments, there is a compound of formula (I''), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is one, two, or three R ^8s . It is a 6-membered heteroaryl optionally substituted with a group. In some embodiments, there is a compound of formula (I''), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is one, two, or three R ^8s . It is a 6-membered heteroaryl optionally substituted with a group, where the 6-membered heteroaryl is selected from pyridinyl, pyrimidinyl, pyrazinyl, pyridadinyl, and triazineyl. In some embodiments, there is a compound of formula (I''), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is optionally at one or two R ⁸ groups. Substituted 6-membered heteroaryl, where the 6-membered heteroaryl is selected from pyridinyl and pyrimidinyl. In some embodiments, there is a compound of formula (I''), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is optionally at one or two R ⁸ units. It is a substituted pyridinyl. In some embodiments, there is a compound of formula (I''), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is optionally at one or two R ⁸ units. It is a substituted pyrimidinyl. In some embodiments, there is a compound of formula (I''), or a pharmaceutically acceptable salt or solvate thereof, wherein R8 is independently halogen, —C ⁽ O). It is selected from OR ¹⁰ , C _1-6 alkyl, and -C _1-6 alkyl-C (O) OR ¹⁰ . In some embodiments, there are compounds of formula (I''), or pharmaceutically acceptable salts or solvates thereof, wherein each R ⁸ is independently −C (O) OR ¹⁰ . Is selected from. In some embodiments, there are compounds of formula (I''), or pharmaceutically acceptable salts or solvates thereof, wherein R ¹ is oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl. , Tetrazolyl, and an unsubstituted 5-membered heteroaryl selected from isoxazolyl. In some embodiments, there is a compound of formula (I''), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is an unsubstituted 6 selected from pyridinyl and pyrimidinyl. It is a member heteroaryl.

In some embodiments, there is a compound of formula (I ″), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is −C (O) N (R ¹⁰ ) ₂ . be. In some embodiments, there is a compound of formula (I ″), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is −C (O) N (R ¹⁰ ) ₂ . Yes, R ¹⁰ are independently H, C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, -C _1-6 alkyl-C _3-8 cycloalkyl, phenyl, -C ₁ Selected from _-6 alkyl-phenyl, and C _2-9 heteroaryl, where C _1-6 alkyl, phenyl, -C _1-6 alkyl-phenyl, and C _2-9 heteroaryl are halogen, C ₁ It is optionally substituted with one or two groups independently selected from _-6alkyl , -N (R ¹¹ ) ₂ , and -C (O) OR ¹² . In some embodiments, there is a compound of formula (I ″), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is −C (O) N (R ¹⁰ ) ₂ . Yes, R ¹⁰ is independently selected from H, C _1-6 alkyl, C _3-8 cycloalkyl, phenyl, and C _2-9 heteroaryl, where C _1-6 alkyl, phenyl, and The C _2-9 heteroaryl is independently substituted with one or two groups selected from halogen, C _1-6 alkyl, -N (R ¹¹ ) ₂ , and -C (O) OR ¹² . In some embodiments, there is a compound of formula (I ″), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is −C (O) N (R ¹⁰ ) ₂ . Yes, R ¹⁰ is independently selected from H, and C _1-6 alkyl optionally substituted with —C (O) OR ¹² . In some embodiments, there is a compound of formula (I ″), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is −C (O) N (R ¹⁰ ) ₂ . Yes, R ¹⁰ is independently selected from H, and C _1-6 alkyl optionally substituted with —C (O) OH. In some embodiments, there is a compound of formula (I ″), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is −C (O) N (R ¹⁰ ) ₂ . Yes, the two ^R10s , and the nitrogen atom to which they are attached, together are one, two, or three independently selected from C _1-6 alkyl, oxo, and -C (O) OH. A 5- or 6-membered heterocycloalkyl ring optionally substituted with one group is formed. In some embodiments, there is a compound of formula (I ″), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is −C (O) N (R ¹⁰ ) ₂ . Yes, the two ^R10s , and the nitrogen atom to which they bind, together form a 5-membered heterocycloalkyl ring substituted with -C (O) OH. In some embodiments, there is a compound of formula (I ″), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is −C (O) N (R ¹⁰ ) ₂ . Yes, the two ^R10s , and the nitrogen atom to which they bind, together form a 6-membered heterocycloalkyl ring substituted with -C (O) OH.

In some embodiments, there is a compound of formula (I ″), or a pharmaceutically acceptable salt or solvate thereof, where R ¹ is −N (R ¹⁰ ) ₂ . In some embodiments, there is a compound of formula (I''), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is −N (R ¹⁰ ) ₂ and R ¹⁰ Are independently H, C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, -C _1-6 alkyl-C _3-8 cycloalkyl, phenyl, -C _1-6 alkyl- Selected from phenyl, and C _2-9 heteroaryl, where C _1-6 alkyl, phenyl, -C _1-6 alkyl-phenyl, and C _2-9 heteroaryl are halogen, C _1-6 alkyl,. It is optionally substituted with one or two groups independently selected from -N (R ¹¹ ) ₂ and -C (O) OR ¹² . In some embodiments, there is a compound of formula (I''), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is −N (R ¹⁰ ) ₂ and R ¹⁰ Are independently selected from H, C _1-6 alkyl, C _3-8 cycloalkyl, phenyl, and C _2-9 heteroaryl, where C _1-6 alkyl, phenyl, and C _2-9 . Heteroaryl is independently substituted with one or two groups selected from halogen, C _1-6 alkyl, -N (R ¹¹ ) ₂ , and -C (O) OR ¹² . In some embodiments, there is a compound of formula (I''), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is −N (R ¹⁰ ) ₂ and R ¹⁰ Are independently selected from H, and C _1-6 alkyl optionally substituted with -C (O) OR ¹² . In some embodiments, there is a compound of formula (I''), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is −N (R ¹⁰ ) ₂ and R ¹⁰ Are independently selected from C _1-6 alkyl optionally substituted with H and -C (O) OH. In some embodiments, there is a compound of formula (I''), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is −N (R ¹⁰ ) ₂ and there are two. The R ¹⁰ , and the nitrogen atoms to which they are attached, together, are optional in one, two, or three groups independently selected from C _1-6 alkyl, oxo, and -C (O) OH. Form a 5- or 6-membered heterocycloalkyl ring substituted with. In some embodiments, there is a compound of formula (I''), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is −N (R ¹⁰ ) ₂ and there are two. R ¹⁰ and the nitrogen atom to which they are attached together form a 5-membered heterocycloalkyl ring substituted with —C (O) OH. In some embodiments, there is a compound of formula (I''), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is −N (R ¹⁰ ) ₂ and there are two. R ¹⁰ and the nitrogen atom to which they are attached together form a 6-membered heterocycloalkyl ring substituted with —C (O) OH.

In some embodiments, there is a compound of formula (I''), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is —C (O) OH.

In some embodiments, there is a compound of formula (I ″), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is −CH ₂ C (O) OH.

In some embodiments, there are compounds of formula (I''), or pharmaceutically acceptable salts or solvates thereof, wherein R ¹ is -C (O) NHS (O) ₂ N ( R ¹⁰ ) ₂ .

In some embodiments, there is a compound of formula (I''), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is:

である。

Is.

In some embodiments, there is a compound of formula (I''), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is:

である。いくつかの実施形態では、式（Ｉ’’）の化合物、またはその薬学的に許容可能な塩あるいは溶媒和物があり、ここで、Ｒ^１は、

Is. In some embodiments, there is a compound of formula (I''), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is:

であり、ｍは２である。いくつかの実施形態では、式（Ｉ’’）の化合物、またはその薬学的に許容可能な塩あるいは溶媒和物があり、ここで、Ｒ^１は、

And m is 2. In some embodiments, there is a compound of formula (I''), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is:

であり、ｍは１である。

And m is 1.

In some embodiments, there is a compound of formula (I''), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is −CH ₂ R ⁴ and R ⁴ is.

である。いくつかの実施形態では、式（Ｉ’’）の化合物、またはその薬学的に許容可能な塩あるいは溶媒和物があり、ここで、Ｒ^１は－ＣＨ_２Ｒ^４であり、Ｒ^４は、

Is. In some embodiments, there is a compound of formula (I''), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is −CH ₂ R ⁴ and R ⁴ is.

であり、ｑは０である。いくつかの実施形態では、式（Ｉ’’）の化合物、またはその薬学的に許容可能な塩あるいは溶媒和物があり、ここで、Ｒ^１は－ＣＨ_２Ｒ^４であり、Ｒ^４は、

And q is 0. In some embodiments, there is a compound of formula (I''), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is −CH ₂ R ⁴ and R ⁴ is.

であり、ｑは０であり、Ｒ^６は－Ｃ（Ｏ）ＯＲ^７である。いくつかの実施形態では、式（Ｉ’’）の化合物、またはその薬学的に許容可能な塩あるいは溶媒和物があり、ここで、Ｒ^１は－ＣＨ_２Ｒ^４であり、Ｒ^４は、

, Q is 0, and R ⁶ is −C (O) OR ⁷ . In some embodiments, there is a compound of formula (I''), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is −CH ₂ R ⁴ and R ⁴ is.

であり、ｑは０であり、Ｒ^６は－Ｃ（Ｏ）ＯＨである。いくつかの実施形態では、式（Ｉ’’）の化合物、またはその薬学的に許容可能な塩あるいは溶媒和物があり、ここで、Ｒ^１は－ＣＨ_２Ｒ^４であり、Ｒ^４は、

, Q is 0, and R ⁶ is −C (O) OH. In some embodiments, there is a compound of formula (I''), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is −CH ₂ R ⁴ and R ⁴ is.

であり、ｑは０であり、Ｒ^６は－Ｃ（Ｏ）ＮＨＳ（Ｏ）_２Ｎ（Ｒ^１０）_２である。いくつかの実施形態では、式（Ｉ’’）の化合物、またはその薬学的に許容可能な塩あるいは溶媒和物があり、ここで、Ｒ^１は－ＣＨ_２Ｒ^４であり、Ｒ^４は、

, Q is 0, and R ⁶ is −C (O) NHS (O) ₂ N (R ¹⁰ ) ₂ . In some embodiments, there is a compound of formula (I''), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is −CH ₂ R ⁴ and R ⁴ is.

であり、ｑは０であり、Ｒ^６は、

, Q is 0, and R ⁶ is

である。いくつかの実施形態では、式（Ｉ’’）の化合物、またはその薬学的に許容可能な塩あるいは溶媒和物があり、ここで、Ｒ^１は－ＣＨ_２Ｒ^４であり、Ｒ^４は、

Is. In some embodiments, there is a compound of formula (I''), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is −CH ₂ R ⁴ and R ⁴ is.

であり、ｑは０であり、Ｒ^６は、

, Q is 0, and R ⁶ is

である。

Is.

In some embodiments, there is a compound of formula (I''), or a pharmaceutically acceptable salt or solvate thereof, wherein R ² is H, —OH, —N (R ¹⁰ ). ₂ or —OC _1-6 alkyl. In some embodiments, there is a compound of formula (I ″), or a pharmaceutically acceptable salt or solvate thereof, wherein R ² is —OC _1-6 alkyl. In some embodiments, there is a compound of formula (I ″), or a pharmaceutically acceptable salt or solvate thereof, wherein R ² is —OCH ₂ CH ₃ . In some embodiments, there is a compound of formula (I''), or a pharmaceutically acceptable salt or solvate thereof, wherein R ² is H. In some embodiments, there is a compound of formula (I''), or a pharmaceutically acceptable salt or solvate thereof, wherein R ² is —OH. In some embodiments, there is a compound of formula (I ″), or a pharmaceutically acceptable salt or solvate thereof, wherein R ² is −N (R ¹⁰ ) ₂ .

In some embodiments, there is a compound of formula (I ″), or a pharmaceutically acceptable salt or solvate thereof, where n is 0.

In some embodiments, there are compounds of formula (I''), or pharmaceutically acceptable salts or solvates thereof, where n is 1, 2, or 3. In some embodiments, there is a compound of formula (I''), or a pharmaceutically acceptable salt or solvate thereof, where n is 1, 2, or 3 and R ³ is. Halogen, -CN, -OR ⁹ , -N (R ¹⁰ ) ₂ , -S (O) ₂ R ⁹ , -NHS (O) ₂ R ⁹ , -S (O) ₂ N (R ¹⁰ ) independently ) ₂ , -C (O) R ⁹ , -C (O) OR ¹⁰ , -OC (O) R ⁹ , -C (O) N (R ¹⁰ ) ₂ , -NR ¹⁰ C (O) N (R ¹⁰ ) ) ₂ , -NR ¹⁰ C (O) R ⁹ , C _1-6 alkyl, -C _1-6 alkyl-OH, -C _1-6 alkyl-OR ⁹ , -C _1-6 alkyl-N (R ¹⁰ ) ₂ , C _1-6 haloalkyl, C _3-8 cycloalkyl, and -C _1-6 alkyl-C _3-8 cycloalkyl are selected. In some embodiments, there is a compound of formula (I''), or a pharmaceutically acceptable salt or solvate thereof, where n is 1, 2, or 3 and R ³ is. Independently selected from halogen, -OR ⁹ , -N (R ¹⁰ ) ₂ , -C (O) OR ¹⁰ , -C (O) N (R ¹⁰ ) ₂ , and C _1-6 alkyl. In some embodiments, there is a compound of formula (I''), or a pharmaceutically acceptable salt or solvate thereof, where n is 1, 2, or 3 and R ³ is. Independently selected from halogens and C _1-6 alkyls, respectively. In some embodiments, there is a compound of formula (I''), or a pharmaceutically acceptable salt or solvate thereof, where n is 1. In some embodiments, there is a compound of formula (I''), or a pharmaceutically acceptable salt or solvate thereof, where n is 1 and R ³ is a halogen, —OH,. -OR ⁹ , -N (R ¹⁰ ) ₂ , C _1-6 alkyl, -C _1-6 alkyl-OH, -C _1-6 alkyl-OR ⁹ , and C _1-6 haloalkyl are selected. In some embodiments, there is a compound of formula (I''), or a pharmaceutically acceptable salt or solvate thereof, where n is 1 and R ³ is a halogen, —OR ⁹ , And C _1-6 alkyl. In some embodiments, there is a compound of formula (I''), or a pharmaceutically acceptable salt or solvate thereof, where n is 1 and R ³ is a halogen, —OR ⁹ , And C _1-6 alkyl. In some embodiments, there is a compound of formula (I''), or a pharmaceutically acceptable salt or solvate thereof, where n is 1 and R ³ is −OR ⁹ . In some embodiments, there is a compound of formula (I''), or a pharmaceutically acceptable salt or solvate thereof, where n is 1 and R ³ is −OR ⁹ . R ⁹ is C _3-8 cycloalkyl. In some embodiments, there is a compound of formula (I''), or a pharmaceutically acceptable salt or solvate thereof, where n is 1 and R ³ is −OR ⁹ . R ⁹ is cyclopentyl.

In some embodiments, compounds of formula (I'), or pharmaceutically acceptable salts or solvates thereof, are provided herein:

式中、
Ｒ^１は、－ＣＨ_２Ｒ^４、－ＣＮ、－Ｂ（ＯＨ）_２、－Ｎ（Ｒ^１０）_２、－ＮＲ^１０Ｃ（Ｏ）Ｒ^９、－Ｃ（Ｏ）ＯＨ、－ＣＨ_２Ｃ（Ｏ）ＯＨ、－Ｃ（Ｏ）Ｎ（Ｒ^１０）_２、－Ｃ（Ｏ）ＮＨＳ（Ｏ）_２Ｎ（Ｒ^１０）_２、－Ｃ_１－６アルキル－ＯＨ、Ｃ_３－８シクロアルキル、

During the ceremony
R ¹ is -CH ₂ R ⁴ , -CN, -B (OH) ₂ , -N (R ¹⁰ ) ₂ , -NR ¹⁰ C (O) R ⁹ , -C (O) OH, -CH ₂ C ( O) OH, -C (O) N (R ¹⁰ ) ₂ , -C (O) NHS (O) ₂ N (R ¹⁰ ) ₂ , -C _1-6 alkyl-OH, C _3-8 cycloalkyl,

、あるいは１つ、２つ、または３つのＲ^８基で随意に置換された５員または６員のヘテロアリールであり；
Ｒ^２は、Ｈ、－ＯＨ、－Ｎ（Ｒ^１０）_２、－ＮＨＳ（Ｏ）_２Ｒ^９、－Ｓ（Ｏ）_２Ｎ（Ｒ^１０）_２、－Ｃ（Ｏ）Ｎ（Ｒ^１０）_２、－ＯＣ（Ｏ）Ｎ（Ｒ^１０）_２、－Ｏ－Ｃ_１－６アルキル、－Ｃ_１－６アルキル－ＯＨ、－Ｃ_１－６アルキル－ＯＲ^９、－Ｃ_１－６アルキル－Ｎ（Ｒ^１０）_２、Ｃ_２－６アルケニル、Ｃ_２－６アルキニル、Ｃ_１－６ハロアルキル、Ｃ_３－８シクロアルキルであり；
Ｒ^３はそれぞれ独立して、ハロゲン、－ＣＮ、－ＯＨ、－ＯＲ^９、－ＳＲ^９、－Ｎ（Ｒ^１０）_２、－Ｓ（Ｏ）Ｒ^９、－Ｓ（Ｏ）_２Ｒ^９、－ＮＨＳ（Ｏ）_２Ｒ^９、－Ｓ（Ｏ）_２Ｎ（Ｒ^１０）_２、－Ｃ（Ｏ）Ｒ^９、－Ｃ（Ｏ）ＯＲ^１０、－ＯＣ（Ｏ）Ｒ^９、－Ｃ（Ｏ）Ｎ（Ｒ^１０）_２、－ＯＣ（Ｏ）Ｎ（Ｒ^１０）_２、－ＮＲ^１０Ｃ（Ｏ）Ｎ（Ｒ^１０）_２、－ＮＲ^１０Ｃ（Ｏ）Ｒ^９、－ＮＲ^１０Ｃ（Ｏ）ＯＲ^９、Ｃ_１－６アルキル、－Ｃ_１－６アルキル－ＯＨ、－Ｃ_１－６アルキル－ＯＲ^９、－Ｃ_１－６アルキル－Ｎ（Ｒ^１０）_２、Ｃ_２－６アルケニル、Ｃ_２－６アルキニル、Ｃ_１－６ハロアルキル、Ｃ_３－８シクロアルキル、および－Ｃ_１－６アルキル－Ｃ_３－８シクロアルキルから選択され；
Ｒ^４は、

, Or a 5- or ⁶ -membered heteroaryl optionally substituted with one, two, or three R8 groups;
R ² is H, -OH, -N (R ¹⁰ ) ₂ , -NHS (O) ₂ R ⁹ , -S (O) ₂ N (R ¹⁰ ) ₂ , -C (O) N (R ¹⁰ ) ₂ , -OC (O) N (R ¹⁰ ) ₂ , -OC _1-6 alkyl, -C _1-6 alkyl-OH, -C _1-6 alkyl-OR ⁹ , -C _1-6 alkyl-N ( R ¹⁰ ) ₂ , C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _3-8 cycloalkyl;
R ³ are independently halogen, -CN, -OH, -OR ⁹ , -SR ⁹ , -N (R ¹⁰ ) ₂ , -S (O) R ⁹ , -S (O) ₂ R ⁹ ,- NHS (O) ₂ R ⁹ , -S (O) ₂ N (R ¹⁰ ) ₂ , -C (O) R ⁹ , -C (O) OR ¹⁰ , -OC (O) R ⁹ , -C (O) N (R ¹⁰ ) ₂ , -OC (O) N (R ¹⁰ ) ₂ , -NR ¹⁰ C (O) N (R ¹⁰ ) ₂ , -NR ¹⁰ C (O) R ⁹ , -NR ¹⁰ C (O) OR ⁹ , C _1-6 alkyl, -C _1-6 alkyl-OH, -C _1-6 alkyl-OR ⁹ , -C _1-6 alkyl-N (R ¹⁰ ) ₂ , C _2-6 alkenyl, C ₂ Selected from _-6 alkynyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, and -C _1-6 alkyl-C _3-8 cycloalkyl;
^R4 is

であり；
Ｒ^５はそれぞれ独立して、ハロゲン、－ＣＮ、－ＯＨ、－ＯＲ^９、－ＳＲ^９、－Ｎ（Ｒ^１０）_２、－Ｓ（Ｏ）Ｒ^９、－Ｓ（Ｏ）_２Ｒ^９、－ＮＨＳ（Ｏ）_２Ｒ^９、－Ｓ（Ｏ）_２Ｎ（Ｒ^１０）_２、－Ｃ（Ｏ）ＮＨＳ（Ｏ）_２Ｎ（Ｒ^１０）_２、－Ｃ（Ｏ）Ｒ^９、－Ｃ（Ｏ）ＯＲ^１０、－ＯＣ（Ｏ）Ｒ^９、－Ｃ（Ｏ）Ｎ（Ｒ^１０）_２、－ＯＣ（Ｏ）Ｎ（Ｒ^１０）_２、－ＮＲ^１０Ｃ（Ｏ）Ｎ（Ｒ^１０）_２、－ＮＲ^１０Ｃ（Ｏ）Ｒ^９、－ＮＲ^１０Ｃ（Ｏ）ＯＲ^９、Ｃ_１－６アルキル、－Ｃ_１－６アルキル－Ｒ^９、－Ｃ_１－６アルキル－ＯＨ、－Ｃ_１－６アルキル－ＯＲ^９、－Ｃ_１－６アルキル－Ｎ（Ｒ^１０）_２、－Ｃ_１－６アルキル－Ｃ（Ｏ）ＯＲ^１０、Ｃ_２－６アルケニル、－Ｃ_２－６アルケニル－Ｃ（Ｏ）ＯＲ^１０、Ｃ_２－６アルキニル、Ｃ_１－６ハロアルキル、Ｃ_１－６ハロアルキル－ＯＨ、Ｃ_３－８シクロアルキル、－Ｃ_１－６アルキル－Ｃ_３－８シクロアルキル、フェニル、－Ｃ_１－６アルキル－フェニル、Ｃ_２－９ヘテロシクロアルキル、およびＣ_１－９ヘテロアリールから選択され；ここで、フェニル、－Ｃ_１－６アルキル－フェニル、およびＣ_１－９ヘテロアリールは、ハロゲン、Ｃ_１－６アルキル、Ｃ_１－６ハロアルキル、Ｃ_３－８シクロアルキル、およびＣ_２－９ヘテロシクロアルキルから独立して選択される１つ、２つ、または３つの基で随意に置換され；ならびにここで、Ｃ_２－９ヘテロシクロアルキルは、ハロゲン、Ｃ_１－６アルキル、Ｃ_１－６ハロアルキル、およびオキソから独立して選択される１つ、２つ、または３つの基で随意に置換され；
Ｒ^６は、－Ｃ（Ｏ）ＯＲ^７、－Ｃ（Ｏ）ＮＨＳ（Ｏ）_２Ｎ（Ｒ^１０）_２、

And;
R ⁵ are independently halogen, -CN, -OH, -OR ⁹ , -SR ⁹ , -N (R ¹⁰ ) ₂ , -S (O) R ⁹ , -S (O) ₂ R ⁹ ,- NHS (O) ₂ R ⁹ , -S (O) ₂ N (R ¹⁰ ) ₂ , -C (O) NHS (O) ₂ N (R ¹⁰ ) ₂ , -C (O) R ⁹ , -C (O) ) OR ¹⁰ , -OC (O) R ⁹ , -C (O) N (R ¹⁰ ) ₂ , -OC (O) N (R ¹⁰ ) ₂ , -NR ¹⁰ C (O) N (R ¹⁰ ) ₂ , -NR ¹⁰ C (O) R ⁹ , -NR ¹⁰ C (O) OR ⁹ , C _1-6 alkyl, -C _1-6 alkyl-R ⁹ , -C _1-6 alkyl-OH, -C _1-6 Alkyl-OR ⁹ , -C _1-6 Alkyl-N (R ¹⁰ ) ₂ , -C _1-6 Alkyl-C (O) OR ¹⁰ , C _2-6 Alkenyl, -C _2-6 Alkenyl-C (O) OR ¹⁰ , C _2-6 alkynyl, C _1-6 haloalkyl, C _1-6 haloalkyl-OH, C _3-8 cycloalkyl, -C _1-6 alkyl-C _3-8 cycloalkyl, phenyl, -C _1- Selected from ₆ Alkyl-Phenyl, C _2-9 Heterocycloalkyl, and C _1-9 Heteroaryl; where phenyl, -C _1-6 Alkyl-Phenyl, and C _1-9 Heteroaryl are halogens, C. Arbitrarily substituted with one, two, or three groups independently selected from _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, and C _2-9 heterocycloalkyl; and Here, the C _2-9 heterocycloalkyl is optionally substituted with one, two, or three groups independently selected from halogen, C _1-6 alkyl, C _1-6 haloalkyl, and oxo. ;
R ⁶ is -C (O) OR ⁷ , -C (O) NHS (O) ₂ N (R ¹⁰ ) ₂ ,

であり；
Ｒ^７はそれぞれ独立して、ＨおよびＣ_１－６アルキルから選択され；
Ｒ^８はそれぞれ独立して、ハロゲン、－ＯＨ、－ＯＲ^９、－Ｎ（Ｒ^１０）_２、－Ｓ（Ｏ）Ｒ^９、－Ｓ（Ｏ）_２Ｒ^９、－ＮＨＳ（Ｏ）_２Ｒ^９、－Ｓ（Ｏ）_２Ｎ（Ｒ^１０）_２、－Ｃ（Ｏ）ＮＨＳ（Ｏ）_２Ｎ（Ｒ^１０）_２、－Ｃ（Ｏ）Ｒ^９、－Ｃ（Ｏ）ＯＲ^１０、－ＯＣ（Ｏ）Ｒ^９、－Ｃ（Ｏ）Ｎ（Ｒ^１０）_２、－ＯＣ（Ｏ）Ｎ（Ｒ^１０）_２、－ＮＲ^１０Ｃ（Ｏ）Ｎ（Ｒ^１０）_２、－ＮＲ^１０Ｃ（Ｏ）Ｒ^９、－ＮＲ^１０Ｃ（Ｏ）ＯＲ^９、Ｃ_１－６アルキル、－Ｃ_１－６アルキル－ＯＨ、－Ｃ_１－６アルキル－ＯＲ^９、－Ｃ_１－６アルキル－Ｎ（Ｒ^１０）_２、－Ｃ_１－６アルキル－Ｃ（Ｏ）ＯＲ^１０、Ｃ_１－６ハロアルキル、Ｃ_１－６ハロアルキル－ＯＨ、Ｃ_３－８シクロアルキル、－Ｃ_１－６アルキル－Ｃ_３－８シクロアルキル、フェニル、－Ｃ_１－６アルキル－フェニル、Ｃ_２－９ヘテロシクロアルキル、およびＣ_１－９ヘテロアリールから選択され；ここで、フェニル、－Ｃ_１－６アルキル－フェニル、およびＣ_１－９ヘテロアリールは、ハロゲン、Ｃ_１－６アルキル、Ｃ_１－６ハロアルキル、Ｃ_３－８シクロアルキル、およびＣ_２－９ヘテロシクロアルキルから独立して選択される１つ、２つ、または３つの基で随意に置換され；ならびにここで、Ｃ_２－９ヘテロシクロアルキルは、ハロゲン、Ｃ_１－６アルキル、Ｃ_１－６ハロアルキル、およびオキソから独立して選択される１つ、２つ、または３つの基で随意に置換され；
Ｒ^９はそれぞれ独立して、Ｃ_１－６アルキル、Ｃ_１－６ハロアルキル、Ｃ_３－８シクロアルキル、－Ｃ_１－６アルキル－Ｃ_３－８シクロアルキル、フェニル、－Ｃ_１－６アルキル－フェニル、Ｃ_２－９ヘテロシクロアルキル、－Ｃ_１－６アルキル－Ｃ_２－９ヘテロシクロアルキル、Ｃ_２－９ヘテロアリール、および－Ｃ_１－６アルキル－Ｃ_２－９ヘテロアリールから選択され、ここで、Ｃ_１－６アルキル、フェニル、－Ｃ_１－６アルキル－フェニル、－Ｃ_１－６アルキル－Ｃ_２－９ヘテロシクロアルキル、Ｃ_２－９ヘテロアリール、および－Ｃ_１－６アルキル－Ｃ_２－９ヘテロアリールは、Ｃ_１－６アルキル、－ＯＲ１１、－Ｎ（Ｒ^１１）_２、Ｃ_１－６アルキル、Ｃ_３－８シクロアルキル、－Ｎ（Ｒ^１１）Ｃ（Ｏ）Ｒ^１２、－Ｃ（Ｏ）Ｒ^１２、および－Ｃ（Ｏ）ＯＲ^１２から独立して選択される１つまたは２つの基で随意に置換され；
Ｒ^１０はそれぞれ独立して、Ｈ、Ｃ_１－６アルキル、Ｃ_１－６ハロアルキル、Ｃ_３－８シクロアルキル、－Ｃ_１－６アルキル－Ｃ_３－８シクロアルキル、フェニル、－Ｃ_１－６アルキル－フェニル、およびＣ_２－９ヘテロアリールから選択され、ここで、Ｃ_１－６アルキル、フェニル、－Ｃ_１－６アルキル－フェニル、およびＣ_２－９ヘテロアリールは、ハロゲン、Ｃ_１－６アルキル、－Ｎ（Ｒ^１１）_２、および－Ｃ（Ｏ）ＯＲ^１２から独立して選択される１つまたは２つの基で随意に置換され；あるいは、２つのＲ^１０、およびそれらが結合している窒素原子は一緒になって、Ｃ_１－６アルキル、オキソ、および－Ｃ（Ｏ）ＯＨから独立して選択される１つ、２つ、または３つの基で随意に置換された５員または６員のヘテロシクロアルキル環を形成し；
Ｒ^１１はそれぞれ独立して、ＨおよびＣ_１－６アルキルから選択され；
Ｒ^１２は独立して、ＨおよびＣ_１－６アルキルから選択され；
ｎは、０、１、２、または３であり；
ｐは、０、１、２、３、４、または５であり；および、
ｑは、０、１、２、３、または４である。

And;
^R7 is independently selected from H and C _1-6 alkyl;
R ⁸ are independently halogen, -OH, -OR ⁹ , -N (R ¹⁰ ) ₂ , -S (O) R ⁹ , -S (O) ₂ R ⁹ , -NHS (O) ₂ R ⁹ , -S (O) ₂ N (R ¹⁰ ) ₂ , -C (O) NHS (O) ₂ N (R ¹⁰ ) ₂ , -C (O) R ⁹ , -C (O) OR ¹⁰ , -OC ( O) R ⁹ , -C (O) N (R ¹⁰ ) ₂ , -OC (O) N (R ¹⁰ ) ₂ , -NR ¹⁰ C (O) N (R ¹⁰ ) ₂ , -NR ¹⁰ C (O) R ⁹ , -NR ¹⁰ C (O) OR ⁹ , C _1-6 alkyl, -C _1-6 alkyl-OH, -C _1-6 alkyl-OR ⁹ , -C _1-6 alkyl-N (R ¹⁰ ) ₂ , -C _1-6 alkyl-C (O) OR ¹⁰ , C _1-6 haloalkyl, C _1-6 haloalkyl-OH, C _3-8 cycloalkyl, -C _1-6 alkyl-C _3-8 cycloalkyl , Phenyl, -C _1-6 alkyl-phenyl, C _2-9 heterocycloalkyl, and C _1-9 heteroaryl; where phenyl, -C _1-6 alkyl-phenyl, and C _1-9 Heteroaryl is one, two or three groups independently selected from halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, and C _2-9 heterocycloalkyl. And where C _2-9 heterocycloalkyl is selected independently of halogen, C _1-6 alkyl, C _1-6 haloalkyl, and oxo, one, two, or three. Arbitrarily replaced by one group;
R ⁹ are independently C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, -C _1-6 alkyl-C _3-8 cycloalkyl, phenyl, -C _1-6 alkyl- Selected from phenyl, C _2-9 heterocycloalkyl, -C _1-6 alkyl-C _2-9 heterocycloalkyl, C _2-9 heteroaryl, and -C _1-6 alkyl-C _2-9 heteroaryl, Here, C _1-6 alkyl, phenyl, -C _1-6 alkyl-phenyl, -C _1-6 alkyl-C _2-9 heterocycloalkyl, C _2-9 heteroaryl, and -C _1-6 alkyl- C _2-9 heteroaryls are C _1-6 alkyl, -OR 11, -N (R ¹¹ ) ₂ , C _1-6 alkyl, C _3-8 cycloalkyl, -N (R ¹¹ ) C (O) R ¹² , -C (O) R ¹² , and -C (O) OR ¹² optionally substituted with one or two groups selected independently;
R ¹⁰ are independently H, C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, -C _1-6 alkyl-C _3-8 cycloalkyl, phenyl, -C _1-6 . Selected from alkyl-phenyl and C _2-9 heteroaryl, where C _1-6 alkyl, phenyl, -C _1-6 alkyl-phenyl, and C _2-9 heteroaryl are halogen, C _1-6 . It is optionally substituted with one or two groups independently selected from alkyl, -N (R ¹¹ ) ₂ , and -C (O) OR ¹² ; or two R ^10s , and they are combined. The nitrogen atoms present together are 5-membered or optionally substituted with one, two, or three groups independently selected from C _1-6 alkyl, oxo, and -C (O) OH. Forming a 6-membered heterocycloalkyl ring;
R ¹¹ is independently selected from H and C _1-6 alkyl;
^R12 is independently selected from H and C _1-6 alkyl;
n is 0, 1, 2, or 3;
p is 0, 1, 2, 3, 4, or 5; and
q is 0, 1, 2, 3, or 4.

In some embodiments, there are compounds of formula (I'), or pharmaceutically acceptable salts or solvates thereof, wherein R ¹ is:

である。いくつかの実施形態では、式（Ｉ’）の化合物、またはその薬学的に許容可能な塩あるいは溶媒和物があり、ここで、Ｒ^１は、

Is. In some embodiments, there are compounds of formula (I'), or pharmaceutically acceptable salts or solvates thereof, wherein R ¹ is:

であり、ｐは、０、１、または２である。いくつかの実施形態では、式（Ｉ’）の化合物、またはその薬学的に許容可能な塩あるいは溶媒和物があり、ここで、Ｒ^１は、

And p is 0, 1, or 2. In some embodiments, there are compounds of formula (I'), or pharmaceutically acceptable salts or solvates thereof, wherein R ¹ is:

であり、ｐは０である。いくつかの実施形態では、式（Ｉ’）の化合物、またはその薬学的に許容可能な塩あるいは溶媒和物があり、ここで、Ｒ^１は、

And p is 0. In some embodiments, there are compounds of formula (I'), or pharmaceutically acceptable salts or solvates thereof, wherein R ¹ is:

であり、ｐは１である。いくつかの実施形態では、式（Ｉ’）の化合物、またはその薬学的に許容可能な塩あるいは溶媒和物があり、ここで、Ｒ^１は、

And p is 1. In some embodiments, there are compounds of formula (I'), or pharmaceutically acceptable salts or solvates thereof, wherein R ¹ is:

であり、ｐは２である。いくつかの実施形態では、式（Ｉ’）の化合物、またはその薬学的に許容可能な塩あるいは溶媒和物があり、ここで、Ｒ^１は、

And p is 2. In some embodiments, there are compounds of formula (I'), or pharmaceutically acceptable salts or solvates thereof, wherein R ¹ is:

であり、ｐは１または２である。いくつかの実施形態では、式（Ｉ’）の化合物、またはその薬学的に許容可能な塩あるいは溶媒和物があり、ここで、Ｒ^１は、

And p is 1 or 2. In some embodiments, there are compounds of formula (I'), or pharmaceutically acceptable salts or solvates thereof, wherein R ¹ is:

であり、ｐは１または２であり、Ｒ^５はそれぞれ独立して、ハロゲン、－ＯＨ、－ＯＲ^９、－Ｎ（Ｒ^１０）_２、－Ｓ（Ｏ）_２Ｒ^９、－ＮＨＳ（Ｏ）_２Ｒ^９、－Ｓ（Ｏ）_２Ｎ（Ｒ^１０）_２、－Ｃ（Ｏ）ＮＨＳ（Ｏ）_２Ｎ（Ｒ^１０）_２、－Ｃ（Ｏ）Ｒ^９、－Ｃ（Ｏ）ＯＲ^１０、－ＯＣ（Ｏ）Ｒ^９、－Ｃ（Ｏ）Ｎ（Ｒ^１０）_２、－ＯＣ（Ｏ）Ｎ（Ｒ^１０）_２、－ＮＲ^１０Ｃ（Ｏ）Ｎ（Ｒ^１０）_２、－ＮＲ^１０Ｃ（Ｏ）Ｒ^９、Ｃ_１－６アルキル、－Ｃ_１－６アルキル－ＯＨ、－Ｃ_１－６アルキル－ＯＲ^９、－Ｃ_１－６アルキル－Ｎ（Ｒ^１０）_２、－Ｃ_１－６アルキル－Ｃ（Ｏ）ＯＲ^１０、Ｃ_１－６ハロアルキル、Ｃ_１－６ハロアルキル－ＯＨ、Ｃ_３－８シクロアルキル、Ｃ_２－９ヘテロシクロアルキル、およびＣ_１－９ヘテロアリールから選択される。いくつかの実施形態では、式（Ｉ’）の化合物、またはその薬学的に許容可能な塩あるいは溶媒和物があり、ここで、Ｒ^１は、

, P is 1 or 2, and R ⁵ is independent of halogen, -OH, -OR ⁹ , -N (R ¹⁰ ) ₂ , -S (O) ₂ R ⁹ , -NHS (O). ₂ R ⁹ , -S (O) ₂ N (R ¹⁰ ) ₂ , -C (O) NHS (O) ₂ N (R ¹⁰ ) ₂ , -C (O) R ⁹ , -C (O) OR ¹⁰ , -OC (O) R ⁹ , -C (O) N (R ¹⁰ ) ₂ , -OC (O) N (R ¹⁰ ) ₂ , -NR ¹⁰ C (O) N (R ¹⁰ ) ₂ , -NR ¹⁰ C (O) R ⁹ , C _1-6 alkyl, -C _1-6 alkyl-OH, -C _1-6 alkyl-OR ⁹ , -C _1-6 alkyl-N (R ¹⁰ ) ₂ , -C _1-6 It is selected from alkyl-C (O) OR ¹⁰ , C _1-6 haloalkyl, C _1-6 haloalkyl-OH, C _3-8 cycloalkyl, C _2-9 heterocycloalkyl, and C _1-9 heteroaryl. In some embodiments, there are compounds of formula (I'), or pharmaceutically acceptable salts or solvates thereof, wherein R ¹ is:

であり、ｐは、１または２であり、Ｒ^５はそれぞれ独立して、ハロゲン、－ＯＨ、－ＯＲ^９、－Ｎ（Ｒ^１０）_２、－Ｓ（Ｏ）_２Ｒ^９、－ＮＨＳ（Ｏ）_２Ｒ^９、－Ｓ（Ｏ）_２Ｎ（Ｒ^１０）_２、－Ｃ（Ｏ）ＮＨＳ（Ｏ）_２Ｎ（Ｒ^１０）_２、－Ｃ（Ｏ）Ｒ^９、－Ｃ（Ｏ）ＯＲ^１０、－ＯＣ（Ｏ）Ｒ^９、－Ｃ（Ｏ）Ｎ（Ｒ^１０）_２、－ＯＣ（Ｏ）Ｎ（Ｒ^１０）_２、－ＮＲ^１０Ｃ（Ｏ）Ｎ（Ｒ^１０）_２、－ＮＲ^１０Ｃ（Ｏ）Ｒ^９、Ｃ_１－６アルキル、－Ｃ_１－６アルキル－ＯＨ、－Ｃ_１－６アルキル－ＯＲ^９、－Ｃ_１－６アルキル－Ｎ（Ｒ^１０）_２、－Ｃ_１－６アルキル－Ｃ（Ｏ）ＯＲ^１０、Ｃ_１－６ハロアルキル、Ｃ_１－６ハロアルキル－ＯＨ、Ｃ_３－８シクロアルキル、Ｃ_２－９ヘテロシクロアルキル、およびＣ_１－９ヘテロアリールから選択され、Ｒ^１０はそれぞれ独立して、ＨおよびＣ_１－６アルキルから選択される。いくつかの実施形態では、式（Ｉ’）の化合物、またはその薬学的に許容可能な塩あるいは溶媒和物があり、ここで、Ｒ^１は、

, P is 1 or 2, and R ⁵ is independently halogen, -OH, -OR ⁹ , -N (R ¹⁰ ) ₂ , -S (O) ₂ R ⁹ , -NHS (O). ) ₂ R ⁹ , -S (O) ₂ N (R ¹⁰ ) ₂ , -C (O) NHS (O) ₂ N (R ¹⁰ ) ₂ , -C (O) R ⁹ , -C (O) OR ¹⁰ , -OC (O) R ⁹ , -C (O) N (R ¹⁰ ) ₂ , -OC (O) N (R ¹⁰ ) ₂ , -NR ¹⁰ C (O) N (R ¹⁰ ) ₂ , -NR ¹⁰ C (O) R ⁹ , C _1-6 alkyl, -C _1-6 alkyl-OH, -C _1-6 alkyl-OR ⁹ , -C _1-6 alkyl-N (R ¹⁰ ) ₂ , -C _1- Selected from _6alkyl -C (O) OR ¹⁰ , C _1-6 haloalkyl, C _1-6 haloalkyl-OH, C _3-8 cycloalkyl, C _2-9 heterocycloalkyl, and C _1-9 heteroaryl. R ¹⁰ is independently selected from H and C _1-6 alkyl. In some embodiments, there are compounds of formula (I'), or pharmaceutically acceptable salts or solvates thereof, wherein R ¹ is:

であり、ｐは、１または２であり、Ｒ^５はそれぞれ独立して、ハロゲン、－ＯＨ、－ＯＲ^９、－Ｎ（Ｒ^１０）_２、－Ｃ（Ｏ）ＮＨＳ（Ｏ）_２Ｎ（Ｒ^１０）_２、－Ｃ（Ｏ）ＯＲ^１０、－Ｃ（Ｏ）Ｎ（Ｒ^１０）_２、－ＮＲ^１０Ｃ（Ｏ）Ｒ^９、Ｃ_１－６アルキル、－Ｃ_１－６アルキル－Ｃ（Ｏ）ＯＲ^１０、およびＣ_１－９ヘテロアリールから選択される。いくつかの実施形態では、式（Ｉ’）の化合物、またはその薬学的に許容可能な塩あるいは溶媒和物があり、ここで、Ｒ^１は、

, P is 1 or 2, and R ⁵ is independently halogen, -OH, -OR ⁹ , -N (R ¹⁰ ) ₂ , -C (O) NHS (O) ₂ N (R). ¹⁰ ) ₂ , -C (O) OR ¹⁰ , -C (O) N (R ¹⁰ ) ₂ , -NR ¹⁰ C (O) R ⁹ , C _1-6 alkyl, -C _1-6 alkyl-C (O) ) OR ¹⁰ and C _1-9 heteroaryls. In some embodiments, there are compounds of formula (I'), or pharmaceutically acceptable salts or solvates thereof, wherein R ¹ is:

であり、ｐは１または２であり、Ｒ^５はそれぞれ独立して、ハロゲン、－ＯＨ、－ＯＲ^９、－Ｎ（Ｒ^１０）_２、－Ｃ（Ｏ）ＮＨＳ（Ｏ）_２Ｎ（Ｒ^１０）_２、－Ｃ（Ｏ）ＯＲ^１０、－Ｃ（Ｏ）Ｎ（Ｒ^１０）_２、－ＮＲ^１０Ｃ（Ｏ）Ｒ^９、Ｃ_１－６アルキル、－Ｃ_１－６アルキル－Ｃ（Ｏ）ＯＲ^１０、およびＣ_１－９ヘテロアリールから選択され、Ｒ^１０はそれぞれ独立して、ＨおよびＣ_１－６アルキルから選択される。いくつかの実施形態では、式（Ｉ’）の化合物、またはその薬学的に許容可能な塩あるいは溶媒和物があり、ここで、Ｒ^１は、

, P is 1 or 2, and R ⁵ is independent of halogen, -OH, -OR ⁹ , -N (R ¹⁰ ) ₂ , -C (O) NHS (O) ₂ N (R ¹⁰ ). ) ₂ , -C (O) OR ¹⁰ , -C (O) N (R ¹⁰ ) ₂ , -NR ¹⁰ C (O) R ⁹ , C _1-6 alkyl, -C _1-6 alkyl-C (O) Selected from OR ¹⁰ and C _1-9 heteroaryl, R ¹⁰ is independently selected from H and C _1-6 alkyl, respectively. In some embodiments, there are compounds of formula (I'), or pharmaceutically acceptable salts or solvates thereof, wherein R ¹ is:

であり、ｐは１または２であり、Ｒ^５はそれぞれ独立して、－ＯＲ^９、－Ｃ（Ｏ）ＯＲ^１０、－Ｃ（Ｏ）Ｎ（Ｒ^１０）_２、Ｃ_１－６アルキル、－Ｃ_１－６アルキル－Ｃ（Ｏ）ＯＲ^１０から選択される。いくつかの実施形態では、式（Ｉ’）の化合物、またはその薬学的に許容可能な塩あるいは溶媒和物があり、ここで、Ｒ^１は、

, P is 1 or 2, and R ⁵ is independently -OR ⁹ , -C (O) OR ¹⁰ , -C (O) N (R ¹⁰ ) ₂ , C _1-6 alkyl,-, respectively. It is selected from C _1-6 alkyl-C (O) OR ¹⁰ . In some embodiments, there are compounds of formula (I'), or pharmaceutically acceptable salts or solvates thereof, wherein R ¹ is:

であり、ｐは１または２であり、Ｒ^５はそれぞれ独立して、－ＯＲ^９、－Ｃ（Ｏ）ＯＲ^１０、－Ｃ（Ｏ）Ｎ（Ｒ^１０）_２、Ｃ_１－６アルキル、－Ｃ_１－６アルキル－Ｃ（Ｏ）ＯＲ^１０から選択され、Ｒ^１０はそれぞれ独立して、ＨおよびＣ_１－６アルキルから選択される。いくつかの実施形態では、式（Ｉ’）の化合物、またはその薬学的に許容可能な塩あるいは溶媒和物があり、ここで、Ｒ^１は、

, P is 1 or 2, and R ⁵ is independently -OR ⁹ , -C (O) OR ¹⁰ , -C (O) N (R ¹⁰ ) ₂ , C _1-6 alkyl,-, respectively. Selected from C _1-6 alkyl-C (O) OR ¹⁰ , R ¹⁰ is independently selected from H and C _1-6 alkyl. In some embodiments, there are compounds of formula (I'), or pharmaceutically acceptable salts or solvates thereof, wherein R ¹ is:

であり、ｐは１または２であり、Ｒ^５はそれぞれ独立して、－Ｃ（Ｏ）ＯＲ^１０から選択される。いくつかの実施形態では、式（Ｉ’）の化合物、またはその薬学的に許容可能な塩あるいは溶媒和物があり、ここで、Ｒ^１は、

, P is 1 or 2, and R ⁵ is independently selected from -C (O) OR ¹⁰ . In some embodiments, there are compounds of formula (I'), or pharmaceutically acceptable salts or solvates thereof, wherein R ¹ is:

であり、ｐは１または２であり、Ｒ^５はそれぞれ独立して、－Ｃ（Ｏ）ＯＲ^１０から選択され、Ｒ^１０はそれぞれ独立して、ＨおよびＣ_１－６アルキルから選択される。いくつかの実施形態では、式（Ｉ’）の化合物、またはその薬学的に許容可能な塩あるいは溶媒和物があり、ここで、Ｒ^１は、

And p is 1 or 2, R ⁵ is independently selected from -C (O) OR ¹⁰ , and R ¹⁰ is independently selected from H and C _1-6 alkyl. In some embodiments, there are compounds of formula (I'), or pharmaceutically acceptable salts or solvates thereof, wherein R ¹ is:

であり、ｐは１または２であり、Ｒ^５はそれぞれ独立して、－ＯＨ、－ＯＲ^９、および－Ｃ_１－６アルキル－Ｃ（Ｏ）ＯＲ^１０から選択される。いくつかの実施形態では、式（Ｉ’）の化合物、またはその薬学的に許容可能な塩あるいは溶媒和物があり、ここで、Ｒ^１は、

, P is 1 or 2, and R ⁵ is independently selected from -OH, -OR ⁹ , and -C _1-6 alkyl-C (O) OR ¹⁰ . In some embodiments, there are compounds of formula (I'), or pharmaceutically acceptable salts or solvates thereof, wherein R ¹ is:

であり、ｐは１または２であり、Ｒ^５はそれぞれ独立して、－ＯＨ、－ＯＲ^９、および－Ｃ_１－６アルキル－Ｃ（Ｏ）ＯＲ^１０から選択され、Ｒ^９は、－Ｃ（Ｏ）ＯＲ^１２で随意に置換されたＣ_１－６アルキルである。いくつかの実施形態では、式（Ｉ’）の化合物、またはその薬学的に許容可能な塩あるいは溶媒和物があり、ここで、Ｒ^１は、

And p is 1 or 2, R ⁵ is independently selected from -OH, -OR ⁹ and -C _1-6 alkyl-C (O) OR ¹⁰ , and R ⁹ is -C. (O) C _1-6 alkyl optionally substituted with OR ¹² . In some embodiments, there are compounds of formula (I'), or pharmaceutically acceptable salts or solvates thereof, wherein R ¹ is:

であり、ｐは１であり、Ｒ^５は独立して、－Ｃ（Ｏ）ＯＨから選択される。

, P is ¹ , and R5 is independently selected from -C (O) OH.

In some embodiments, there are compounds of formula (I'), or pharmaceutically acceptable salts or solvates thereof, wherein R ¹ is 1, 2, or 3 R ⁸ groups. It is a 5- or 6-membered heteroaryl optionally substituted with. In some embodiments, there are compounds of formula (I'), or pharmaceutically acceptable salts or solvates thereof, wherein R ¹ is 1, 2, or 3 R ⁸ groups. It is a 5-membered heteroaryl optionally substituted with. In some embodiments, there are compounds of formula (I'), or pharmaceutically acceptable salts or solvates thereof, wherein R ¹ is 1, 2, or 3 R ⁸ groups. The 5-membered heteroaryls optionally substituted in, where the 5-membered heteroaryls are oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, and thiadiazolyl. Is selected from. In some embodiments, there are compounds of formula (I'), or pharmaceutically acceptable salts or solvates thereof, wherein R ¹ is optionally substituted with one or two R ⁸ groups. The 5-membered heteroaryl is here selected from oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, tetrazolyl, and isoxazolyl. In some embodiments, there are compounds of formula (I'), or pharmaceutically acceptable salts or solvates thereof, wherein R ¹ is optionally substituted with one or two R ⁸ groups. Oxazolyl. In some embodiments, there are compounds of formula (I'), or pharmaceutically acceptable salts or solvates thereof, wherein R ¹ is optionally substituted with one or two R ⁸ groups. It is thiazolyl. In some embodiments, there are compounds of formula (I'), or pharmaceutically acceptable salts or solvates thereof, wherein R ¹ is optionally substituted with one or two R ⁸ groups. It is a pyrazolyl that has been used. In some embodiments, there are compounds of formula (I'), or pharmaceutically acceptable salts or solvates thereof, wherein R ¹ is optionally substituted with one or two R ⁸ groups. It is a solvent that has been made. In some embodiments, there are compounds of formula (I'), or pharmaceutically acceptable salts or solvates thereof, wherein R ¹ is optionally substituted with one or two R ⁸ groups. It is a thienil that has been made. In some embodiments, there are compounds of formula (I'), or pharmaceutically acceptable salts or solvates thereof, wherein R ¹ is optionally substituted with one or two R ⁸ groups. It is a pyrollyl that has been made. In some embodiments, there are compounds of formula (I'), or pharmaceutically acceptable salts or solvates thereof, wherein R ¹ is optionally substituted with one or two R ⁸ groups. It is a tetrazolyl that has been used. In some embodiments, there are compounds of formula (I'), or pharmaceutically acceptable salts or solvates thereof, wherein R ¹ is optionally substituted with one or two R ⁸ groups. Isoxazolyl. In some embodiments, there are compounds of formula (I'), or pharmaceutically acceptable salts or solvates thereof, wherein R ¹ is 1, 2, or 3 R ⁸ groups. It is a 6-membered heteroaryl optionally substituted with. In some embodiments, there are compounds of formula (I'), or pharmaceutically acceptable salts or solvates thereof, wherein R ¹ is 1, 2, or 3 R ⁸ groups. 6-membered heteroaryl optionally substituted in, where the 6-membered heteroaryl is selected from pyridinyl, pyrimidinyl, pyrazinyl, pyridadinyl, and triazinyl. In some embodiments, there are compounds of formula (I'), or pharmaceutically acceptable salts or solvates thereof, wherein R ¹ is optionally substituted with one or two R ⁸ groups. 6-membered heteroaryl, wherein the 6-membered heteroaryl is selected from pyridinyl and pyrimidinyl. In some embodiments, there are compounds of formula (I'), or pharmaceutically acceptable salts or solvates thereof, wherein R ¹ is optionally substituted with one or two R ⁸ groups. It is a pyridinyl that has been used. In some embodiments, there are compounds of formula (I'), or pharmaceutically acceptable salts or solvates thereof, wherein R ¹ is optionally substituted with one or two R ⁸ groups. It is pyrimidinyl. In some embodiments, there are compounds of formula (I'), or pharmaceutically acceptable salts or solvates thereof, wherein the R ^8s are independently halogen, —C (O) OR. ¹⁰ , C _1-6 alkyl, and -C _1-6 alkyl-C (O) OR ¹⁰ are selected. In some embodiments, there are compounds of formula (I'), or pharmaceutically acceptable salts or solvates thereof, wherein each R ⁸ is independently from -C (O) OR ¹⁰ . Be selected. In some embodiments, there are compounds of formula (I'), or pharmaceutically acceptable salts or solvates thereof, wherein R ¹ is oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, It is an unsubstituted 5-membered heteroaryl selected from tetrazolyl and isoxazolyl. In some embodiments, there is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is an unsubstituted 6 member selected from pyridinyl and pyrimidinyl. Heteroaryl.

In some embodiments, there is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is -C (O) N (R ¹⁰ ) ₂ . .. In some embodiments, there is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is -C (O) N (R ¹⁰ ) ₂ . , R ¹⁰ are independently H, C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, -C _1-6 alkyl-C _3-8 cycloalkyl, phenyl, -C _{1- 6} Alkyl-Phenyl, and C _2-9 Heteroaryl are selected, where C _1-6 Alkyl, Phenyl, -C _1-6 Alkyl-Phenyl, and C _2-9 Heteroaryl are halogen, C _1- . It is optionally substituted with one or two groups independently selected from ₆ alkyl, -N (R ¹¹ ) ₂ , and -C (O) OR ¹² . In some embodiments, there is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is -C (O) N (R ¹⁰ ) ₂ . , R ¹⁰ are independently selected from H, C _1-6 alkyl, C _3-8 cycloalkyl, phenyl, and C _2-9 heteroaryl, where C _1-6 alkyl, phenyl, and C. _{The 2-9} heteroaryl is independently substituted with one or two groups selected from halogen, C _1-6 alkyl, -N (R ¹¹ ) ₂ , and -C (O) OR ¹² . In some embodiments, there is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is -C (O) N (R ¹⁰ ) ₂ . , R ¹⁰ are independently selected from H, and C _1-6 alkyl optionally substituted with —C (O) OR ¹² . In some embodiments, there is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is -C (O) N (R ¹⁰ ) ₂ . , R ¹⁰ are independently selected from C _1-6 alkyl optionally substituted with H, and —C (O) OH, respectively. In some embodiments, there is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is -C (O) N (R ¹⁰ ) ₂ . The two ^R10s , and the nitrogen atom to which they are attached, together are one, two, or three independently selected from C _1-6 alkyl, oxo, and -C (O) OH. It forms a 5- or 6-membered heterocycloalkyl ring optionally substituted with a group. In some embodiments, there is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is -C (O) N (R ¹⁰ ) ₂ . The two ^R10s , and the nitrogen atom to which they bind, together form a 5-membered heterocycloalkyl ring substituted with —C (O) OH. In some embodiments, there is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is -C (O) N (R ¹⁰ ) ₂ . The two ^R10s , and the nitrogen atom to which they bind, together form a 6-membered heterocycloalkyl ring substituted with —C (O) OH.

In some embodiments, there is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is -N (R ¹⁰ ) ₂ . In some embodiments, there is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is -N (R ¹⁰ ) ₂ and R ¹⁰ is. H, C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, -C _1-6 alkyl-C _3-8 cycloalkyl, phenyl, -C _1-6 alkyl-phenyl, respectively. , And C _2-9 heteroaryl, where C _1-6 alkyl, phenyl, -C _1-6 alkyl-phenyl, and C _2-9 heteroaryl are halogen, C _1-6 alkyl,-. It is optionally substituted with one or two groups independently selected from N (R ¹¹ ) ₂ and -C (O) OR ¹² . In some embodiments, there is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is -N (R ¹⁰ ) ₂ and R ¹⁰ is. Each independently is selected from H, C _1-6 alkyl, C _3-8 cycloalkyl, phenyl, and C _2-9 heteroaryl, where C _1-6 alkyl, phenyl, and C _2-9 hetero Aryl is independently substituted with one or two groups selected from halogen, C _1-6 alkyl, -N (R ¹¹ ) ₂ , and -C (O) OR ¹² . In some embodiments, there is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is -N (R ¹⁰ ) ₂ and R ¹⁰ is. Each independently is selected from H, and C _1-6 alkyl optionally substituted with -C (O) OR ¹² . In some embodiments, there is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is -N (R ¹⁰ ) ₂ and R ¹⁰ is. Each independently is selected from C _1-6 alkyl optionally substituted with H and —C (O) OH. In some embodiments, there is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is -N (R ¹⁰ ) ₂ and the two R are. ¹⁰ , and the nitrogen atoms to which they are attached, together, are optionally in one, two, or three groups independently selected from C _1-6 alkyl, oxo, and -C (O) OH. It forms a substituted 5- or 6-membered heterocycloalkyl ring. In some embodiments, there is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is -N (R ¹⁰ ) ₂ and the two R are. The ¹⁰ and the nitrogen atoms to which they are attached together form a 5-membered heterocycloalkyl ring substituted with -C (O) OH. In some embodiments, there is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is -N (R ¹⁰ ) ₂ and the two R are. The ¹⁰ and the nitrogen atoms to which they are attached together form a 6-membered heterocycloalkyl ring substituted with -C (O) OH.

In some embodiments, there is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is —C (O) OH.

In some embodiments, there are compounds of formula (I'), or pharmaceutically acceptable salts or solvates thereof, wherein R ¹ is -CH ₂ C (O) OH.

In some embodiments, there are compounds of formula (I'), or pharmaceutically acceptable salts or solvates thereof, wherein R ¹ is -C (O) NHS (O) ₂ N (R). ¹⁰ ) ₂ .

In some embodiments, there are compounds of formula (I'), or pharmaceutically acceptable salts or solvates thereof, wherein R ¹ is:

である。

Is.

In some embodiments, there is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is -CH ₂ R ⁴ and R ⁴ is.

である。いくつかの実施形態では、式（Ｉ’）の化合物、またはその薬学的に許容可能な塩あるいは溶媒和物があり、ここで、Ｒ^１は－ＣＨ_２Ｒ^４であり、Ｒ^４は、

Is. In some embodiments, there is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is -CH ₂ R ⁴ and R ⁴ is.

であり、ｑは０である。いくつかの実施形態では、式（Ｉ’）の化合物、またはその薬学的に許容可能な塩あるいは溶媒和物があり、ここで、Ｒ^１は－ＣＨ_２Ｒ^４であり、Ｒ^４は、

And q is 0. In some embodiments, there is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is -CH ₂ R ⁴ and R ⁴ is.

であり、ｑは０であり、Ｒ^６は－Ｃ（Ｏ）ＯＲ^７である。いくつかの実施形態では、式（Ｉ’）の化合物、またはその薬学的に許容可能な塩あるいは溶媒和物があり、ここで、Ｒ^１は－ＣＨ_２Ｒ^４であり、Ｒ^４は、

, Q is 0, and R ⁶ is −C (O) OR ⁷ . In some embodiments, there is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is -CH ₂ R ⁴ and R ⁴ is.

であり、ｑは０であり、Ｒ^６は－Ｃ（Ｏ）ＯＨである。いくつかの実施形態では、式（Ｉ’）の化合物、またはその薬学的に許容可能な塩あるいは溶媒和物があり、ここで、Ｒ^１は－ＣＨ_２Ｒ^４であり、Ｒ^４は、

, Q is 0, and R ⁶ is −C (O) OH. In some embodiments, there is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is -CH ₂ R ⁴ and R ⁴ is.

であり、ｑは０であり、Ｒ^６は－Ｃ（Ｏ）ＮＨＳ（Ｏ）_２Ｎ（Ｒ^１０）_２である。いくつかの実施形態では、式（Ｉ’）の化合物、またはその薬学的に許容可能な塩あるいは溶媒和物があり、ここで、Ｒ^１は－ＣＨ_２Ｒ^４であり、Ｒ^４は、

, Q is 0, and R ⁶ is −C (O) NHS (O) ₂ N (R ¹⁰ ) ₂ . In some embodiments, there is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is -CH ₂ R ⁴ and R ⁴ is.

であり、ｑは０であり、Ｒ^６は、

, Q is 0, and R ⁶ is

である。いくつかの実施形態では、式（Ｉ’）の化合物、またはその薬学的に許容可能な塩あるいは溶媒和物があり、ここで、Ｒ^１は－ＣＨ_２Ｒ^４であり、Ｒ^４は、

Is. In some embodiments, there is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is -CH ₂ R ⁴ and R ⁴ is.

であり、ｑは０であり、Ｒ^６は、

, Q is 0, and R ⁶ is

である。

Is.

In some embodiments, there are compounds of formula (I'), or pharmaceutically acceptable salts or solvates thereof, wherein R ² is H, —OH, —N (R ¹⁰ ) ₂ . , Or —OC _1-6 alkyl. In some embodiments, there are compounds of formula (I'), or pharmaceutically acceptable salts or solvates thereof, wherein R ² is —OC _1-6 alkyl. In some embodiments, there is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R ² is —OCH ₂ CH ₃ . In some embodiments, there is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R ² is H. In some embodiments, there are compounds of formula (I'), or pharmaceutically acceptable salts or solvates thereof, wherein R ² is —OH. In some embodiments, there is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R ² is −N (R ¹⁰ ) ₂ .

In some embodiments, there are compounds of formula (I'), or pharmaceutically acceptable salts or solvates thereof, where n is 0.

In some embodiments, there are compounds of formula (I'), or pharmaceutically acceptable salts or solvates thereof, where n is 1, 2, or 3. In some embodiments, there is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, where n is 1, 2, or 3 and R ³ is R 3 respectively. Independently, halogen, -CN, -OR ⁹ , -N (R ¹⁰ ) ₂ , -S (O) ₂ R ⁹ , -NHS (O) ₂ R ⁹ , -S (O) ₂ N (R ¹⁰ ) ₂ , -C (O) R ⁹ , -C (O) OR ¹⁰ , -OC (O) R ⁹ , -C (O) N (R ¹⁰ ) ₂ , -NR ¹⁰ C (O) N (R ¹⁰ ) ₂ , -NR ¹⁰ C (O) R ⁹ , C _1-6 alkyl, -C _1-6 alkyl-OH, -C _1-6 alkyl-OR ⁹ , -C _1-6 alkyl-N (R ¹⁰ ) ₂ , C _1-6 haloalkyl, C _3-8 cycloalkyl, and -C _1-6 alkyl-C _3-8 cycloalkyl. In some embodiments, there is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, where n is 1, 2, or 3 and R ³ is R 3 respectively. Independently selected from halogen, -OR ⁹ , -N (R ¹⁰ ) ₂ , -C (O) OR ¹⁰ , -C (O) N (R ¹⁰ ) ₂ , and C _1-6 alkyl. In some embodiments, there is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, where n is 1, 2, or 3 and R ³ is R 3 respectively. Independently selected from halogens and C _1-6 alkyls. In some embodiments, there is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, where n is 1. In some embodiments, there is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, where n is 1 and R ³ is halogen, —OH, −. It is selected from OR ⁹ , -N (R ¹⁰ ) ₂ , C _1-6 alkyl, -C _1-6 alkyl-OH, -C _1-6 alkyl-OR ⁹ , and C _1-6 haloalkyl. In some embodiments, there is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, where n is 1 and R ³ is a halogen, —OR ⁹ , ,. And C _1-6 alkyl. In some embodiments, there is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, where n is 1 and R ³ is a halogen, —OR ⁹ , ,. And C _1-6 alkyl. In some embodiments, there is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, where n is 1 and R ³ is −OR ⁹ . In some embodiments, there is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, where n is 1, R ³ is -OR ⁹ , and R. ⁹ is C _3-8 cycloalkyl. In some embodiments, there is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, where n is 1, R ³ is -OR ⁹ , and R. ⁹ is cyclopentyl.

In some embodiments, compounds of formula (I), or pharmaceutically acceptable salts or solvates thereof, are provided herein.

式中、
Ｒ^１は、－ＣＨ_２Ｒ^４、－ＣＮ、－Ｂ（ＯＨ）_２、－Ｎ（Ｒ^１０）_２、－ＮＲ^１０Ｃ（Ｏ）Ｒ^９、－Ｃ（Ｏ）ＯＨ、－ＣＨ_２Ｃ（Ｏ）ＯＨ、－Ｃ（Ｏ）Ｎ（Ｒ^１０）_２、－Ｃ（Ｏ）ＮＨＳ（Ｏ）_２Ｎ（Ｒ^１０）_２、－Ｃ_１－６アルキル－ＯＨ、Ｃ_３－８シクロアルキル、

During the ceremony
R ¹ is -CH ₂ R ⁴ , -CN, -B (OH) ₂ , -N (R ¹⁰ ) ₂ , -NR ¹⁰ C (O) R ⁹ , -C (O) OH, -CH ₂ C ( O) OH, -C (O) N (R ¹⁰ ) ₂ , -C (O) NHS (O) ₂ N (R ¹⁰ ) ₂ , -C _1-6 alkyl-OH, C _3-8 cycloalkyl,

、あるいは１つ、２つ、または３つのＲ^８基で随意に置換された５員または６員のヘテロアリールであり；
Ｒ^２は、Ｈ、－ＯＨ、－Ｎ（Ｒ^１０）_２、－ＮＨＳ（Ｏ）_２Ｒ^９、－Ｓ（Ｏ）_２Ｎ（Ｒ^１０）_２、－Ｃ（Ｏ）Ｎ（Ｒ^１０）_２、－ＯＣ（Ｏ）Ｎ（Ｒ^１０）_２、－Ｏ－Ｃ_１－６アルキル、－Ｃ_１－６アルキル－ＯＨ、－Ｃ_１－６アルキル－ＯＲ^９、－Ｃ_１－６アルキル－Ｎ（Ｒ^１０）_２、Ｃ_２－６アルケニル、Ｃ_２－６アルキニル、Ｃ_１－６ハロアルキル、Ｃ_３－８シクロアルキルであり；
Ｒ^３はそれぞれ独立して、ハロゲン、－ＣＮ、－ＯＨ、－ＯＲ^９、－ＳＲ^９、－Ｎ（Ｒ^１０）_２、－Ｓ（Ｏ）Ｒ^９、－Ｓ（Ｏ）_２Ｒ^９、－ＮＨＳ（Ｏ）_２Ｒ^９、－Ｓ（Ｏ）_２Ｎ（Ｒ^１０）_２、－Ｃ（Ｏ）Ｒ^９、－Ｃ（Ｏ）ＯＲ^１０、－ＯＣ（Ｏ）Ｒ^９、－Ｃ（Ｏ）Ｎ（Ｒ^１０）_２、－ＯＣ（Ｏ）Ｎ（Ｒ^１０）_２、－ＮＲ^１０Ｃ（Ｏ）Ｎ（Ｒ^１０）_２、－ＮＲ^１０Ｃ（Ｏ）Ｒ^９、－ＮＲ^１０Ｃ（Ｏ）ＯＲ^９、Ｃ_１－６アルキル、－Ｃ_１－６アルキル－ＯＨ、－Ｃ_１－６アルキル－ＯＲ^９、－Ｃ_１－６アルキル－Ｎ（Ｒ^１０）_２、Ｃ_２－６アルケニル、Ｃ_２－６アルキニル、Ｃ_１－６ハロアルキル、Ｃ_３－８シクロアルキル、および－Ｃ_１－６アルキル－Ｃ_３－８シクロアルキルから選択され；
Ｒ^４は、

, Or a 5- or ⁶ -membered heteroaryl optionally substituted with one, two, or three R8 groups;
R ² is H, -OH, -N (R ¹⁰ ) ₂ , -NHS (O) ₂ R ⁹ , -S (O) ₂ N (R ¹⁰ ) ₂ , -C (O) N (R ¹⁰ ) ₂ , -OC (O) N (R ¹⁰ ) ₂ , -OC _1-6 alkyl, -C _1-6 alkyl-OH, -C _1-6 alkyl-OR ⁹ , -C _1-6 alkyl-N ( R ¹⁰ ) ₂ , C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _3-8 cycloalkyl;
R ³ are independently halogen, -CN, -OH, -OR ⁹ , -SR ⁹ , -N (R ¹⁰ ) ₂ , -S (O) R ⁹ , -S (O) ₂ R ⁹ ,- NHS (O) ₂ R ⁹ , -S (O) ₂ N (R ¹⁰ ) ₂ , -C (O) R ⁹ , -C (O) OR ¹⁰ , -OC (O) R ⁹ , -C (O) N (R ¹⁰ ) ₂ , -OC (O) N (R ¹⁰ ) ₂ , -NR ¹⁰ C (O) N (R ¹⁰ ) ₂ , -NR ¹⁰ C (O) R ⁹ , -NR ¹⁰ C (O) OR ⁹ , C _1-6 alkyl, -C _1-6 alkyl-OH, -C _1-6 alkyl-OR ⁹ , -C _1-6 alkyl-N (R ¹⁰ ) ₂ , C _2-6 alkenyl, C ₂ Selected from _-6 alkynyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, and -C _1-6 alkyl-C _3-8 cycloalkyl;
^R4 is

であり；
Ｒ^５はそれぞれ独立して、ハロゲン、－ＣＮ、－ＯＨ、－ＯＲ^９、－ＳＲ^９、－Ｎ（Ｒ^１０）_２、－Ｓ（Ｏ）Ｒ^９、－Ｓ（Ｏ）_２Ｒ^９、－ＮＨＳ（Ｏ）_２Ｒ^９、－Ｓ（Ｏ）_２Ｎ（Ｒ^１０）_２、－Ｃ（Ｏ）ＮＨＳ（Ｏ）_２Ｎ（Ｒ^１０）_２、－Ｃ（Ｏ）Ｒ^９、－Ｃ（Ｏ）ＯＲ^１０、－ＯＣ（Ｏ）Ｒ^９、－Ｃ（Ｏ）Ｎ（Ｒ^１０）_２、－ＯＣ（Ｏ）Ｎ（Ｒ^１０）_２、－ＮＲ^１０Ｃ（Ｏ）Ｎ（Ｒ^１０）_２、－ＮＲ^１０Ｃ（Ｏ）Ｒ^９、－ＮＲ^１０Ｃ（Ｏ）ＯＲ^９、Ｃ_１－６アルキル、－Ｃ_１－６アルキル－ＯＨ、－Ｃ_１－６アルキル－ＯＲ^９、－Ｃ_１－６アルキル－Ｎ（Ｒ^１０）_２、－Ｃ_１－６アルキル－Ｃ（Ｏ）ＯＲ^１０、Ｃ_２－６アルケニル、Ｃ_２－６アルキニル、Ｃ_１－６ハロアルキル、Ｃ_１－６ハロアルキル－ＯＨ、Ｃ_３－８シクロアルキル、－Ｃ_１－６アルキル－Ｃ_３－８シクロアルキル、フェニル、－Ｃ_１－６アルキル－フェニル、Ｃ_２－９ヘテロシクロアルキル、およびＣ_１－９ヘテロアリールから選択され；ここで、フェニル、－Ｃ_１－６アルキル－フェニル、およびＣ_１－９ヘテロアリールは、ハロゲン、Ｃ_１－６アルキル、Ｃ_１－６ハロアルキル、Ｃ_３－８シクロアルキル、およびＣ_２－９ヘテロシクロアルキルから独立して選択される１つ、２つ、または３つの基で随意に置換され；ならびにここで、Ｃ_２－９ヘテロシクロアルキルは、ハロゲン、Ｃ_１－６アルキル、Ｃ_１－６ハロアルキル、およびオキソから独立して選択される１つ、２つ、または３つの基で随意に置換され；
Ｒ^６は、－Ｃ（Ｏ）ＯＲ^７、－Ｃ（Ｏ）ＮＨＳ（Ｏ）_２Ｎ（Ｒ^１０）_２、

And;
R ⁵ are independently halogen, -CN, -OH, -OR ⁹ , -SR ⁹ , -N (R ¹⁰ ) ₂ , -S (O) R ⁹ , -S (O) ₂ R ⁹ ,- NHS (O) ₂ R ⁹ , -S (O) ₂ N (R ¹⁰ ) ₂ , -C (O) NHS (O) ₂ N (R ¹⁰ ) ₂ , -C (O) R ⁹ , -C (O) ) OR ¹⁰ , -OC (O) R ⁹ , -C (O) N (R ¹⁰ ) ₂ , -OC (O) N (R ¹⁰ ) ₂ , -NR ¹⁰ C (O) N (R ¹⁰ ) ₂ , -NR ¹⁰ C (O) R ⁹ , -NR ¹⁰ C (O) OR ⁹ , C _1-6 alkyl, -C _1-6 alkyl-OH, -C _1-6 alkyl-OR ⁹ , -C _1-6 Alkyl-N (R ¹⁰ ) ₂ , -C _1-6 alkyl-C (O) OR ¹⁰ , C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _1-6 haloalkyl-OH, C Selected from _3-8 cycloalkyl, -C _1-6 alkyl-C _3-8 cycloalkyl, phenyl, -C _1-6 alkyl-phenyl, C _2-9 heterocycloalkyl, and C _1-9 heteroaryl; Here, phenyl, -C _1-6 alkyl-phenyl, and C _1-9 heteroaryl are halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, and C _2-9 hetero. It is optionally substituted with one, two, or three groups independently selected from cycloalkyl; and where C _2-9 heterocycloalkyl is halogen, C _1-6 alkyl, C _1-6 . Arbitrarily substituted with one, two, or three groups independently selected from haloalkyl, and oxo;
R ⁶ is -C (O) OR ⁷ , -C (O) NHS (O) ₂ N (R ¹⁰ ) ₂ ,

であり；
Ｒ^７はそれぞれ独立して、ＨおよびＣ_１－６アルキルから選択され；
Ｒ^８はそれぞれ独立して、ハロゲン、－ＯＨ、－ＯＲ^９、－Ｎ（Ｒ^１０）_２、－Ｓ（Ｏ）Ｒ^９、－Ｓ（Ｏ）_２Ｒ^９、－ＮＨＳ（Ｏ）_２Ｒ^９、－Ｓ（Ｏ）_２Ｎ（Ｒ^１０）_２、－Ｃ（Ｏ）ＮＨＳ（Ｏ）_２Ｎ（Ｒ^１０）_２、－Ｃ（Ｏ）Ｒ^９、－Ｃ（Ｏ）ＯＲ^１０、－ＯＣ（Ｏ）Ｒ^９、－Ｃ（Ｏ）Ｎ（Ｒ^１０）_２、－ＯＣ（Ｏ）Ｎ（Ｒ^１０）_２、－ＮＲ^１０Ｃ（Ｏ）Ｎ（Ｒ^１０）_２、－ＮＲ^１０Ｃ（Ｏ）Ｒ^９、－ＮＲ^１０Ｃ（Ｏ）ＯＲ^９、Ｃ_１－６アルキル、－Ｃ_１－６アルキル－ＯＨ、－Ｃ_１－６アルキル－ＯＲ^９、－Ｃ_１－６アルキル－Ｎ（Ｒ^１０）_２、－Ｃ_１－６アルキル－Ｃ（Ｏ）ＯＲ^１０、Ｃ_１－６ハロアルキル、Ｃ_１－６ハロアルキル－ＯＨ、Ｃ_３－８シクロアルキル、－Ｃ_１－６アルキル－Ｃ_３－８シクロアルキル、フェニル、－Ｃ_１－６アルキル－フェニル、Ｃ_２－９ヘテロシクロアルキル、およびＣ_１－９ヘテロアリールから選択され；ここで、フェニル、－Ｃ_１－６アルキル－フェニル、およびＣ_１－９ヘテロアリールは、ハロゲン、Ｃ_１－６アルキル、Ｃ_１－６ハロアルキル、Ｃ_３－８シクロアルキル、およびＣ_２－９ヘテロシクロアルキルから独立して選択される１つ、２つ、または３つの基で随意に置換され；ならびにここで、Ｃ_２－９ヘテロシクロアルキルは、ハロゲン、Ｃ_１－６アルキル、Ｃ_１－６ハロアルキル、およびオキソから独立して選択される１つ、２つ、または３つの基で随意に置換され；
Ｒ^９はそれぞれ独立して、Ｃ_１－６アルキル、Ｃ_１－６ハロアルキル、Ｃ_３－８シクロアルキル、－Ｃ_１－６アルキル－Ｃ_３－８シクロアルキル、フェニル、－Ｃ_１－６アルキル－フェニル、Ｃ_２－９ヘテロシクロアルキル、－Ｃ_１－６アルキル－Ｃ_２－９ヘテロシクロアルキル、Ｃ_２－９ヘテロアリール、および－Ｃ_１－６アルキル－Ｃ_２－９ヘテロアリールから選択され、ここで、Ｃ_１－６アルキル、フェニル、－Ｃ_１－６アルキル－フェニル、－Ｃ_１－６アルキル－Ｃ_２－９ヘテロシクロアルキル、Ｃ_２－９ヘテロアリール、および－Ｃ_１－６アルキル－Ｃ_２－９ヘテロアリールは、Ｃ_１－６アルキル、－ＯＲ１１、－Ｎ（Ｒ^１１）_２、Ｃ_１－６アルキル、Ｃ_３－８シクロアルキル、－Ｃ（Ｏ）Ｒ^１２、および－Ｃ（Ｏ）ＯＲ^１２から独立して選択される１つまたは２つの基で随意に置換され；
Ｒ^１０はそれぞれ独立して、Ｈ、Ｃ_１－６アルキル、Ｃ_１－６ハロアルキル、Ｃ_３－８シクロアルキル、－Ｃ_１－６アルキル－Ｃ_３－８シクロアルキル、フェニル、－Ｃ_１－６アルキル－フェニル、およびＣ_２－９ヘテロアリールから選択され、ここで、Ｃ_１－６アルキル、フェニル、－Ｃ_１－６アルキル－フェニル、およびＣ_２－９ヘテロアリールは、ハロゲン、Ｃ_１－６アルキル、－Ｎ（Ｒ^１１）_２、および－Ｃ（Ｏ）ＯＲ^１２から独立して選択される１つまたは２つの基で随意に置換され；あるいは、２つのＲ^１０、およびそれらが結合している窒素原子は一緒になって、Ｃ_１－６アルキル、オキソ、および－Ｃ（Ｏ）ＯＨから独立して選択される１つ、２つ、または３つの基で随意に置換された５員または６員のヘテロシクロアルキル環を形成し；
Ｒ^１１はそれぞれ独立して、ＨおよびＣ_１－６アルキルから選択され；
Ｒ^１２は独立して、ＨおよびＣ_１－６アルキルから選択され；
ｎは、０、１、２、または３であり；
ｐは、０、１、２、３、４、または５であり；および、
ｑは、０、１、２、３、または４である。

And;
^R7 is independently selected from H and C _1-6 alkyl;
R ⁸ are independently halogen, -OH, -OR ⁹ , -N (R ¹⁰ ) ₂ , -S (O) R ⁹ , -S (O) ₂ R ⁹ , -NHS (O) ₂ R ⁹ , -S (O) ₂ N (R ¹⁰ ) ₂ , -C (O) NHS (O) ₂ N (R ¹⁰ ) ₂ , -C (O) R ⁹ , -C (O) OR ¹⁰ , -OC ( O) R ⁹ , -C (O) N (R ¹⁰ ) ₂ , -OC (O) N (R ¹⁰ ) ₂ , -NR ¹⁰ C (O) N (R ¹⁰ ) ₂ , -NR ¹⁰ C (O) R ⁹ , -NR ¹⁰ C (O) OR ⁹ , C _1-6 alkyl, -C _1-6 alkyl-OH, -C _1-6 alkyl-OR ⁹ , -C _1-6 alkyl-N (R ¹⁰ ) ₂ , -C _1-6 alkyl-C (O) OR ¹⁰ , C _1-6 haloalkyl, C _1-6 haloalkyl-OH, C _3-8 cycloalkyl, -C _1-6 alkyl-C _3-8 cycloalkyl , Phenyl, -C _1-6 alkyl-phenyl, C _2-9 heterocycloalkyl, and C _1-9 heteroaryl; where phenyl, -C _1-6 alkyl-phenyl, and C _1-9 Heteroaryl is one, two or three groups independently selected from halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, and C _2-9 heterocycloalkyl. And where C _2-9 heterocycloalkyl is selected independently of halogen, C _1-6 alkyl, C _1-6 haloalkyl, and oxo, one, two, or three. Arbitrarily replaced by one group;
R ⁹ are independently C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, -C _1-6 alkyl-C _3-8 cycloalkyl, phenyl, -C _1-6 alkyl- Selected from phenyl, C _2-9 heterocycloalkyl, -C _1-6 alkyl-C _2-9 heterocycloalkyl, C _2-9 heteroaryl, and -C _1-6 alkyl-C _2-9 heteroaryl, Here, C _1-6 alkyl, phenyl, -C _1-6 alkyl-phenyl, -C _1-6 alkyl-C _2-9 heterocycloalkyl, C _2-9 heteroaryl, and -C _1-6 alkyl- C _2-9 heteroaryls are C _1-6 alkyl, -OR 11, -N (R ¹¹ ) ₂ , C _1-6 alkyl, C _3-8 cycloalkyl, -C (O) R ¹² , and -C ( O) Optionally substituted with one or two groups independently selected from OR ¹² ;
R ¹⁰ are independently H, C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, -C _1-6 alkyl-C _3-8 cycloalkyl, phenyl, -C _1-6 . Selected from alkyl-phenyl and C _2-9 heteroaryl, where C _1-6 alkyl, phenyl, -C _1-6 alkyl-phenyl, and C _2-9 heteroaryl are halogen, C _1-6 . It is optionally substituted with one or two groups independently selected from alkyl, -N (R ¹¹ ) ₂ , and -C (O) OR ¹² ; or two R ^10s , and they are combined. The nitrogen atoms present together are 5-membered or optionally substituted with one, two, or three groups independently selected from C _1-6 alkyl, oxo, and -C (O) OH. Forming a 6-membered heterocycloalkyl ring;
R ¹¹ is independently selected from H and C _1-6 alkyl;
^R12 is independently selected from H and C _1-6 alkyl;
n is 0, 1, 2, or 3;
p is 0, 1, 2, 3, 4, or 5; and
q is 0, 1, 2, 3, or 4.

In some embodiments, there is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is:

である。いくつかの実施形態では、式（Ｉ）の化合物、またはその薬学的に許容可能な塩あるいは溶媒和物があり、ここで、Ｒ^１は、

Is. In some embodiments, there is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is:

であり、ｐは、０、１、または２である。いくつかの実施形態では、式（Ｉ）の化合物、またはその薬学的に許容可能な塩あるいは溶媒和物があり、ここで、Ｒ^１は、

And p is 0, 1, or 2. In some embodiments, there is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is:

であり、ｐは０である。いくつかの実施形態では、式（Ｉ）の化合物、またはその薬学的に許容可能な塩あるいは溶媒和物があり、ここで、Ｒ^１は、

And p is 0. In some embodiments, there is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is:

であり、ｐは１である。いくつかの実施形態では、式（Ｉ）の化合物、またはその薬学的に許容可能な塩あるいは溶媒和物があり、ここで、Ｒ^１は、

And p is 1. In some embodiments, there is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is:

であり、ｐは２である。いくつかの実施形態では、式（Ｉ）の化合物、またはその薬学的に許容可能な塩あるいは溶媒和物があり、ここで、Ｒ^１は、

And p is 2. In some embodiments, there is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is:

であり、ｐは１または２である。いくつかの実施形態では、式（Ｉ）の化合物、またはその薬学的に許容可能な塩あるいは溶媒和物があり、ここで、Ｒ^１は、

And p is 1 or 2. In some embodiments, there is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is:

であり、ｐは１または２であり、Ｒ^５はそれぞれ独立して、ハロゲン、－ＯＨ、－ＯＲ^９、－Ｎ（Ｒ^１０）_２、－Ｓ（Ｏ）_２Ｒ^９、－ＮＨＳ（Ｏ）_２Ｒ^９、－Ｓ（Ｏ）_２Ｎ（Ｒ^１０）_２、－Ｃ（Ｏ）ＮＨＳ（Ｏ）_２Ｎ（Ｒ^１０）_２、－Ｃ（Ｏ）Ｒ^９、－Ｃ（Ｏ）ＯＲ^１０、－ＯＣ（Ｏ）Ｒ^９、－Ｃ（Ｏ）Ｎ（Ｒ^１０）_２、－ＯＣ（Ｏ）Ｎ（Ｒ^１０）_２、－ＮＲ^１０Ｃ（Ｏ）Ｎ（Ｒ^１０）_２、－ＮＲ^１０Ｃ（Ｏ）Ｒ^９、Ｃ_１－６アルキル、－Ｃ_１－６アルキル－ＯＨ、－Ｃ_１－６アルキル－ＯＲ^９、－Ｃ_１－６アルキル－Ｎ（Ｒ^１０）_２、－Ｃ_１－６アルキル－Ｃ（Ｏ）ＯＲ^１０、Ｃ_１－６ハロアルキル、Ｃ_１－６ハロアルキル－ＯＨ、Ｃ_３－８シクロアルキル、Ｃ_２－９ヘテロシクロアルキル、およびＣ_１－９ヘテロアリールから選択される。いくつかの実施形態では、式（Ｉ）の化合物、またはその薬学的に許容可能な塩あるいは溶媒和物があり、ここで、Ｒ^１は、

, P is 1 or 2, and R ⁵ is independent of halogen, -OH, -OR ⁹ , -N (R ¹⁰ ) ₂ , -S (O) ₂ R ⁹ , -NHS (O). ₂ R ⁹ , -S (O) ₂ N (R ¹⁰ ) ₂ , -C (O) NHS (O) ₂ N (R ¹⁰ ) ₂ , -C (O) R ⁹ , -C (O) OR ¹⁰ , -OC (O) R ⁹ , -C (O) N (R ¹⁰ ) ₂ , -OC (O) N (R ¹⁰ ) ₂ , -NR ¹⁰ C (O) N (R ¹⁰ ) ₂ , -NR ¹⁰ C (O) R ⁹ , C _1-6 alkyl, -C _1-6 alkyl-OH, -C _1-6 alkyl-OR ⁹ , -C _1-6 alkyl-N (R ¹⁰ ) ₂ , -C _1-6 It is selected from alkyl-C (O) OR ¹⁰ , C _1-6 haloalkyl, C _1-6 haloalkyl-OH, C _3-8 cycloalkyl, C _2-9 heterocycloalkyl, and C _1-9 heteroaryl. In some embodiments, there is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is:

であり、ｐは１または２であり、Ｒ^５はそれぞれ独立して、ハロゲン、－ＯＨ、－ＯＲ^９、－Ｎ（Ｒ^１０）_２、－Ｓ（Ｏ）_２Ｒ^９、－ＮＨＳ（Ｏ）_２Ｒ^９、－Ｓ（Ｏ）_２Ｎ（Ｒ^１０）_２、－Ｃ（Ｏ）ＮＨＳ（Ｏ）_２Ｎ（Ｒ^１０）_２、－Ｃ（Ｏ）Ｒ^９、－Ｃ（Ｏ）ＯＲ^１０、－ＯＣ（Ｏ）Ｒ^９、－Ｃ（Ｏ）Ｎ（Ｒ^１０）_２、－ＯＣ（Ｏ）Ｎ（Ｒ^１０）_２、－ＮＲ^１０Ｃ（Ｏ）Ｎ（Ｒ^１０）_２、－ＮＲ^１０Ｃ（Ｏ）Ｒ^９、Ｃ_１－６アルキル、－Ｃ_１－６アルキル－ＯＨ、－Ｃ_１－６アルキル－ＯＲ^９、－Ｃ_１－６アルキル－Ｎ（Ｒ^１０）_２、－Ｃ_１－６アルキル－Ｃ（Ｏ）ＯＲ^１０、Ｃ_１－６ハロアルキル、Ｃ_１－６ハロアルキル－ＯＨ、Ｃ_３－８シクロアルキル、Ｃ_２－９ヘテロシクロアルキル、およびＣ_１－９ヘテロアリールから選択され、Ｒ^１０はそれぞれ独立して、ＨおよびＣ_１－６アルキルから選択される。いくつかの実施形態では、式（Ｉ）の化合物、またはその薬学的に許容可能な塩あるいは溶媒和物があり、ここで、Ｒ^１は、

, P is 1 or 2, and R ⁵ is independent of halogen, -OH, -OR ⁹ , -N (R ¹⁰ ) ₂ , -S (O) ₂ R ⁹ , -NHS (O). ₂ R ⁹ , -S (O) ₂ N (R ¹⁰ ) ₂ , -C (O) NHS (O) ₂ N (R ¹⁰ ) ₂ , -C (O) R ⁹ , -C (O) OR ¹⁰ , -OC (O) R ⁹ , -C (O) N (R ¹⁰ ) ₂ , -OC (O) N (R ¹⁰ ) ₂ , -NR ¹⁰ C (O) N (R ¹⁰ ) ₂ , -NR ¹⁰ C (O) R ⁹ , C _1-6 alkyl, -C _1-6 alkyl-OH, -C _1-6 alkyl-OR ⁹ , -C _1-6 alkyl-N (R ¹⁰ ) ₂ , -C _1-6 Selected from alkyl-C (O) OR ¹⁰ , C _1-6 haloalkyl, C _1-6 haloalkyl-OH, C _3-8 cycloalkyl, C _2-9 heterocycloalkyl, and C _1-9 heteroaryl, R ¹⁰ are independently selected from H and C _1-6 alkyl. In some embodiments, there is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is:

であり、ｐは１または２であり、Ｒ^５はそれぞれ独立して、ハロゲン、－ＯＨ、－ＯＲ^９、－Ｎ（Ｒ^１０）_２、－Ｃ（Ｏ）ＮＨＳ（Ｏ）_２Ｎ（Ｒ^１０）_２、－Ｃ（Ｏ）ＯＲ^１０、－Ｃ（Ｏ）Ｎ（Ｒ^１０）_２、－ＮＲ^１０Ｃ（Ｏ）Ｒ^９、Ｃ_１－６アルキル、－Ｃ_１－６アルキル－Ｃ（Ｏ）ＯＲ^１０、およびＣ_１－９ヘテロアリールから選択される。いくつかの実施形態では、式（Ｉ）の化合物、またはその薬学的に許容可能な塩あるいは溶媒和物があり、ここで、Ｒ^１は、

, P is 1 or 2, and R ⁵ is independent of halogen, -OH, -OR ⁹ , -N (R ¹⁰ ) ₂ , -C (O) NHS (O) ₂ N (R ¹⁰ ). ) ₂ , -C (O) OR ¹⁰ , -C (O) N (R ¹⁰ ) ₂ , -NR ¹⁰ C (O) R ⁹ , C _1-6 alkyl, -C _1-6 alkyl-C (O) It is selected from OR ¹⁰ and C _1-9 heteroaryl. In some embodiments, there is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is:

であり、ｐは１または２であり、Ｒ^５はそれぞれ独立して、ハロゲン、－ＯＨ、－ＯＲ^９、－Ｎ（Ｒ^１０）_２、－Ｃ（Ｏ）ＮＨＳ（Ｏ）_２Ｎ（Ｒ^１０）_２、－Ｃ（Ｏ）ＯＲ^１０、－Ｃ（Ｏ）Ｎ（Ｒ^１０）_２、－ＮＲ^１０Ｃ（Ｏ）Ｒ^９、Ｃ_１－６アルキル、－Ｃ_１－６アルキル－Ｃ（Ｏ）ＯＲ^１０、およびＣ_１－９ヘテロアリールから選択され、Ｒ^１０はそれぞれ独立して、ＨおよびＣ_１－６アルキルから選択される。いくつかの実施形態では、式（Ｉ）の化合物、またはその薬学的に許容可能な塩あるいは溶媒和物があり、ここで、Ｒ^１は、

, P is 1 or 2, and R ⁵ is independent of halogen, -OH, -OR ⁹ , -N (R ¹⁰ ) ₂ , -C (O) NHS (O) ₂ N (R ¹⁰ ). ) ₂ , -C (O) OR ¹⁰ , -C (O) N (R ¹⁰ ) ₂ , -NR ¹⁰ C (O) R ⁹ , C _1-6 alkyl, -C _1-6 alkyl-C (O) Selected from OR ¹⁰ and C _1-9 heteroaryl, R ¹⁰ is independently selected from H and C _1-6 alkyl, respectively. In some embodiments, there is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is:

であり、ｐは１または２であり、Ｒ^５はそれぞれ独立して、－ＯＲ^９、－Ｃ（Ｏ）ＯＲ^１０、－Ｃ（Ｏ）Ｎ（Ｒ^１０）_２、Ｃ_１－６アルキル、－Ｃ_１－６アルキル－Ｃ（Ｏ）ＯＲ^１０から選択される。いくつかの実施形態では、式（Ｉ）の化合物、またはその薬学的に許容可能な塩あるいは溶媒和物があり、ここで、Ｒ^１は、

, P is 1 or 2, and R ⁵ are independently -OR ⁹ , -C (O) OR ¹⁰ , -C (O) N (R ¹⁰ ) ₂ , C _1-6 alkyl,-, respectively. It is selected from C _1-6 alkyl-C (O) OR ¹⁰ . In some embodiments, there is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is:

であり、ｐは１または２であり、Ｒ^５はそれぞれ独立して、－ＯＲ^９、－Ｃ（Ｏ）ＯＲ^１０、－Ｃ（Ｏ）Ｎ（Ｒ^１０）_２、Ｃ_１－６アルキル、－Ｃ_１－６アルキル－Ｃ（Ｏ）ＯＲ^１０から選択され、Ｒ^１０はそれぞれ独立して、ＨおよびＣ_１－６アルキルから選択される。いくつかの実施形態では、式（Ｉ）の化合物、またはその薬学的に許容可能な塩あるいは溶媒和物があり、ここで、Ｒ^１は、

, P is 1 or 2, and R ⁵ is independently -OR ⁹ , -C (O) OR ¹⁰ , -C (O) N (R ¹⁰ ) ₂ , C _1-6 alkyl,-, respectively. Selected from C _1-6 alkyl-C (O) OR ¹⁰ , R ¹⁰ is independently selected from H and C _1-6 alkyl. In some embodiments, there is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is:

であり、ｐは１または２であり、Ｒ^５はそれぞれ独立して、－Ｃ（Ｏ）ＯＲ^１０から選択される。いくつかの実施形態では、式（Ｉ）の化合物、またはその薬学的に許容可能な塩あるいは溶媒和物があり、ここで、Ｒ^１は、

, P is 1 or 2, and R ⁵ is independently selected from -C (O) OR ¹⁰ . In some embodiments, there is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is:

であり、ｐは１または２であり、Ｒ^５はそれぞれ独立して、－Ｃ（Ｏ）ＯＲ^１０から選択され、Ｒ^１０はそれぞれ独立して、ＨおよびＣ_１－６アルキルから選択される。いくつかの実施形態では、式（Ｉ）の化合物、またはその薬学的に許容可能な塩あるいは溶媒和物があり、ここで、Ｒ^１は、

And p is 1 or 2, R ⁵ is independently selected from -C (O) OR ¹⁰ , and R ¹⁰ is independently selected from H and C _1-6 alkyl. In some embodiments, there is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is:

であり、ｐは１または２であり、Ｒ^５はそれぞれ独立して、－ＯＨ、－ＯＲ^９、および－Ｃ_１－６アルキル－Ｃ（Ｏ）ＯＲ^１０から選択される。いくつかの実施形態では、式（Ｉ’’）の化合物、またはその薬学的に許容可能な塩あるいは溶媒和物があり、ここで、Ｒ^１は、

, P is 1 or 2, and R ⁵ is independently selected from -OH, -OR ⁹ , and -C _1-6 alkyl-C (O) OR ¹⁰ . In some embodiments, there is a compound of formula (I''), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is:

であり、ｐは１または２であり、Ｒ^５はそれぞれ独立して、－ＯＨ、－ＯＲ^９、および－Ｃ_１－６アルキル－Ｃ（Ｏ）ＯＲ^１０から選択され、Ｒ^９は、－Ｃ（Ｏ）ＯＲ^１２で随意に置換されたＣ_１－６アルキルである。いくつかの実施形態では、式（Ｉ）の化合物、またはその薬学的に許容可能な塩あるいは溶媒和物があり、ここで、Ｒ^１は、

And p is 1 or 2, R ⁵ is independently selected from -OH, -OR ⁹ and -C _1-6 alkyl-C (O) OR ¹⁰ , and R ⁹ is -C. (O) C _1-6 alkyl optionally substituted with OR ¹² . In some embodiments, there is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is:

であり、ｐは１であり、Ｒ^５は独立して、－Ｃ（Ｏ）ＯＨから選択される。

, P is ¹ , and R5 is independently selected from -C (O) OH.

In some embodiments, there is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is one, two, or three R ⁸ groups. It is a optionally substituted 5- or 6-membered heteroaryl. In some embodiments, there is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is one, two, or three R ⁸ groups. It is a 5-membered heteroaryl optionally substituted. In some embodiments, there is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is 1, 2, or 3 R ⁸ groups. Optionally substituted 5-membered heteroaryls, wherein the 5-membered heteroaryls are from oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, and thiadiazolyl. Be selected. In some embodiments, there is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is optionally substituted with one or two R ⁸ groups. It is a 5-membered heteroaryl, wherein the 5-membered heteroaryl is selected from oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, tetrazolyl, and isoxazolyl. In some embodiments, there is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is optionally substituted with one or two R ⁸ groups. It is oxazolyl. In some embodiments, there is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is optionally substituted with one or two R ⁸ groups. It is a thiazolyl. In some embodiments, there is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is optionally substituted with one or two R ⁸ groups. It is a pyrazolyl. In some embodiments, there is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is optionally substituted with one or two R ⁸ groups. It is a solvent. In some embodiments, there is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is optionally substituted with one or two R ⁸ groups. It is a solvation. In some embodiments, there is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is optionally substituted with one or two R ⁸ groups. It is a solvent. In some embodiments, there is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is optionally substituted with one or two R ⁸ groups. It is tetrazolyl. In some embodiments, there is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is optionally substituted with one or two R ⁸ groups. Isoxazolyl. In some embodiments, there is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is one, two, or three R ⁸ groups. It is a 6-membered heteroaryl optionally substituted. In some embodiments, there is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is one, two, or three R ⁸ groups. It is a optionally substituted 6-membered heteroaryl, wherein the 6-membered heteroaryl is selected from pyridinyl, pyrimidinyl, pyrazinyl, pyridadinyl, and triazineyl. In some embodiments, there is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is optionally substituted with one or two R ⁸ groups. 6-membered heteroaryl, where the 6-membered heteroaryl is selected from pyridinyl and pyrimidinyl. In some embodiments, there is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is optionally substituted with one or two R ⁸ groups. It is a pyridinyl. In some embodiments, there is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is optionally substituted with one or two R ⁸ groups. It is pyrimidinyl. In some embodiments, there is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁸ is independently halogen, —C (O) OR ¹⁰ . , C _1-6 alkyl, and -C _1-6 alkyl-C (O) OR ¹⁰ . In some embodiments, there are compounds of formula (I), or pharmaceutically acceptable salts or solvates thereof, wherein each R ⁸ is independently selected from -C (O) OR ¹⁰ . Will be done. In some embodiments, there is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, tetrazolyl. , And an unsubstituted 5-membered heteroaryl selected from isoxazolyl. In some embodiments, there is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is an unsubstituted 6 member selected from pyridinyl and pyrimidinyl. Heteroaryl.

In some embodiments, there is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is —C (O) N (R ¹⁰ ) ₂ . In some embodiments, there is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is -C (O) N (R ¹⁰ ) ₂ . R ¹⁰ are independently H, C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, -C _1-6 alkyl-C _3-8 cycloalkyl, phenyl, -C _1-6 . Selected from alkyl-phenyl and C _2-9 heteroaryl, where C _1-6 alkyl, phenyl, -C _1-6 alkyl-phenyl, and C _2-9 heteroaryl are halogen, C _1-6 . It is optionally substituted with one or two groups independently selected from alkyl, -N (R ¹¹ ) ₂ , and -C (O) OR ¹² . In some embodiments, there is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is -C (O) N (R ¹⁰ ) ₂ . R ¹⁰ is independently selected from H, C _1-6 alkyl, C _3-8 cycloalkyl, phenyl, and C _2-9 heteroaryl, where C _1-6 alkyl, phenyl, and C ₂ are selected. _-9 heteroaryls are independently substituted with one or two groups selected from halogen, C _1-6 alkyl, -N (R ¹¹ ) ₂ , and -C (O) OR ¹² . In some embodiments, there is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is -C (O) N (R ¹⁰ ) ₂ . R ¹⁰ is independently selected from H and C _1-6 alkyl optionally substituted with —C (O) OR ¹² . In some embodiments, there is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is -C (O) N (R ¹⁰ ) ₂ . R ¹⁰ is independently selected from C _1-6 alkyl optionally substituted with H and —C (O) OH. In some embodiments, there is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is -C (O) N (R ¹⁰ ) ₂ . The two ^R10s , and the nitrogen atom to which they are attached, together are one, two, or three groups independently selected from C _1-6 alkyl, oxo, and -C (O) OH. Form a 5- or 6-membered heterocycloalkyl ring optionally substituted with. In some embodiments, there is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is -C (O) N (R ¹⁰ ) ₂ . The two ^R10s , and the nitrogen atom to which they bind, together form a 5-membered heterocycloalkyl ring substituted with -C (O) OH. In some embodiments, there is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is -C (O) N (R ¹⁰ ) ₂ . The two ^R10s , and the nitrogen atom to which they bind, together form a 6-membered heterocycloalkyl ring substituted with -C (O) OH.

In some embodiments, there is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is −N (R ¹⁰ ) ₂ . In some embodiments, there is a compound of formula (I), or a pharmaceutically acceptable salt or admixture thereof, where R ¹ is −N (R ¹⁰ ) ₂ and R ¹⁰ is each. Independently, H, C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, -C _1-6 alkyl-C _3-8 cycloalkyl, phenyl, -C _1-6 alkyl-phenyl, And C _2-9 heteroaryl, where C _1-6 alkyl, phenyl, -C _1-6 alkyl-phenyl, and C _2-9 heteroaryl are halogen, C _1-6 alkyl, -N. It is optionally substituted with one or two groups independently selected from (R ¹¹ ) ₂ and -C (O) OR ¹² . In some embodiments, there is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, where R ¹ is −N (R ¹⁰ ) ₂ and R ¹⁰ is each. Independently selected from H, C _1-6 alkyl, C _3-8 cycloalkyl, phenyl, and C _2-9 heteroaryl, where C _1-6 alkyl, phenyl, and C _2-9 heteroaryl Is independently substituted with one or two groups selected from halogen, C _1-6 alkyl, -N (R ¹¹ ) ₂ , and -C (O) OR ¹² . In some embodiments, there is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is −N (R ¹⁰ ) ₂ and R ¹⁰ is each. Independently selected from H, and C _1-6 alkyl optionally substituted with -C (O) OR ¹² . In some embodiments, there is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is −N (R ¹⁰ ) ₂ and R ¹⁰ is each. Independently selected from C _1-6 alkyl optionally substituted with H, and —C (O) OH. In some embodiments, there is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is -N (R ¹⁰ ) ₂ and two R ^10s . , And the nitrogen atoms to which they are attached are combined and optionally substituted with one, two, or three groups independently selected from C _1-6 alkyl, oxo, and -C (O) OH. Form a 5- or 6-membered heterocycloalkyl ring. In some embodiments, there is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is -N (R ¹⁰ ) ₂ and two R ^10s . , And the nitrogen atoms to which they bind together form a 5-membered heterocycloalkyl ring substituted with —C (O) OH. In some embodiments, there is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is -N (R ¹⁰ ) ₂ and two R ^10s . , And the nitrogen atoms to which they bind together form a 6-membered heterocycloalkyl ring substituted with —C (O) OH.

In some embodiments, there is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is —C (O) OH.

In some embodiments, there is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is -CH ₂ C (O) OH.

In some embodiments, there is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is -C (O) NHS (O) ₂ N (R ¹⁰ ). ) ₂ .

In some embodiments, there is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is:

である。

Is.

In some embodiments, there is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is -CH ₂ R ⁴ and R ⁴ is.

である。いくつかの実施形態では、式（Ｉ）の化合物、またはその薬学的に許容可能な塩あるいは溶媒和物があり、ここで、Ｒ^１は－ＣＨ_２Ｒ^４であり、Ｒ^４は、

Is. In some embodiments, there is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is -CH ₂ R ⁴ and R ⁴ is.

であり、ｑは０である。いくつかの実施形態では、式（Ｉ）の化合物、またはその薬学的に許容可能な塩あるいは溶媒和物があり、ここで、Ｒ^１は－ＣＨ_２Ｒ^４であり、Ｒ^４は、

And q is 0. In some embodiments, there is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is -CH ₂ R ⁴ and R ⁴ is.

であり、ｑは０であり、Ｒ^６は－Ｃ（Ｏ）ＯＲ^７である。いくつかの実施形態では、式（Ｉ）の化合物、またはその薬学的に許容可能な塩あるいは溶媒和物があり、ここで、Ｒ^１は－ＣＨ_２Ｒ^４であり、Ｒ^４は、

, Q is 0, and R ⁶ is −C (O) OR ⁷ . In some embodiments, there is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is -CH ₂ R ⁴ and R ⁴ is.

であり、ｑは０であり、Ｒ^６は－Ｃ（Ｏ）ＯＨである。いくつかの実施形態では、式（Ｉ）の化合物、またはその薬学的に許容可能な塩あるいは溶媒和物があり、ここで、Ｒ^１は－ＣＨ_２Ｒ^４であり、Ｒ^４は、

, Q is 0, and R ⁶ is −C (O) OH. In some embodiments, there is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is -CH ₂ R ⁴ and R ⁴ is.

であり、ｑは０であり、Ｒ^６は－Ｃ（Ｏ）ＮＨＳ（Ｏ）_２Ｎ（Ｒ^１０）_２である。いくつかの実施形態では、式（Ｉ）の化合物、またはその薬学的に許容可能な塩あるいは溶媒和物があり、ここで、Ｒ^１は－ＣＨ_２Ｒ^４であり、Ｒ^４は、

, Q is 0, and R ⁶ is −C (O) NHS (O) ₂ N (R ¹⁰ ) ₂ . In some embodiments, there is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is -CH ₂ R ⁴ and R ⁴ is.

であり、ｑは０であり、Ｒ^６は、

, Q is 0, and R ⁶ is

である。いくつかの実施形態では、式（Ｉ）の化合物、またはその薬学的に許容可能な塩あるいは溶媒和物があり、ここで、Ｒ^１は－ＣＨ_２Ｒ^４であり、Ｒ^４は、

Is. In some embodiments, there is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is -CH ₂ R ⁴ and R ⁴ is.

であり、ｑは０であり、Ｒ^６は、

, Q is 0, and R ⁶ is

である。

Is.

In some embodiments, there is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ² is H, —OH, —N (R ¹⁰ ) ₂ , Or -OC _1-6 alkyl. In some embodiments, there is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ² is —OC _1-6 alkyl. In some embodiments, there is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ² is —OCH ₂ CH ₃ . In some embodiments, there is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ² is H. In some embodiments, there is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ² is —OH. In some embodiments, there is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ² is −N (R ¹⁰ ) ₂ .

In some embodiments, there is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, where n is 0.

In some embodiments, there is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, where n is 1, 2, or 3. In some embodiments, there is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, where n is 1, 2, or 3 and R ³ is independent of each other. Then, halogen, -CN, -OR ⁹ , -N (R ¹⁰ ) ₂ , -S (O) ₂ R ⁹ , -NHS (O) ₂ R ⁹ , -S (O) ₂ N (R ¹⁰ ) ₂ , -C (O) R ⁹ , -C (O) OR ¹⁰ , -OC (O) R ⁹ , -C (O) N (R ¹⁰ ) ₂ , -NR ¹⁰ C (O) N (R ¹⁰ ) ₂ , -NR ¹⁰ C (O) R ⁹ , C _1-6 alkyl, -C _1-6 alkyl-OH, -C _1-6 alkyl-OR ⁹ , -C _1-6 alkyl-N (R ¹⁰ ) ₂ , It is selected from C _1-6 haloalkyl, C _3-8 cycloalkyl, and -C _1-6 alkyl-C _3-8 cycloalkyl. In some embodiments, there is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, where n is 1, 2, or 3 and R ³ is independent of each other. Then, it is selected from halogen, -OR ⁹ , -N (R ¹⁰ ) ₂ , -C (O) OR ¹⁰ , -C (O) N (R ¹⁰ ) ₂ , and C _1-6 alkyl. In some embodiments, there is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, where n is 1, 2, or 3 and R ³ is independent of each other. It is then selected from halogens and C _1-6 alkyls. In some embodiments, there is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, where n is 1. In some embodiments, there is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, where n is 1 and R ³ is halogen, —OH, —OR. It is selected from ⁹ , -N (R ¹⁰ ) ₂ , C _1-6 alkyl, -C _1-6 alkyl-OH, -C _1-6 alkyl-OR ⁹ , and C _1-6 haloalkyl. In some embodiments, there is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, where n is 1 and R ³ is a halogen, —OR ⁹ and. It is selected from C _1-6 alkyl. In some embodiments, there is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, where n is 1 and R ³ is a halogen, —OR ⁹ and. It is selected from C _1-6 alkyl. In some embodiments, there is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, where n is 1 and R ³ is −OR ⁹ . In some embodiments, there is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, where n is 1, R ³ is -OR ⁹ , and R ⁹ is. Is C _3-8 cycloalkyl. In some embodiments, there is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, where n is 1, R ³ is -OR ⁹ , and R ⁹ is. Is cyclopentyl.

In some embodiments, compounds of formula (Ia), or pharmaceutically acceptable salts or solvates thereof, are provided herein.

式中、
Ｒ^２は、Ｈ、－ＯＨ、－Ｎ（Ｒ^１０）_２、－ＮＨＳ（Ｏ）_２Ｒ^９、－Ｓ（Ｏ）_２Ｎ（Ｒ^１０）_２、－Ｃ（Ｏ）Ｎ（Ｒ^１０）_２、－ＯＣ（Ｏ）Ｎ（Ｒ^１０）_２、－Ｏ－Ｃ_１－６アルキル、－Ｃ_１－６アルキル－ＯＨ、－Ｃ_１－６アルキル－ＯＲ^９、－Ｃ_１－６アルキル－Ｎ（Ｒ^１０）_２、Ｃ_２－６アルケニル、Ｃ_２－６アルキニル、Ｃ_１－６ハロアルキル、Ｃ_３－８シクロアルキルであり；
Ｒ^３はそれぞれ独立して、ハロゲン、－ＣＮ、－ＯＨ、－ＯＲ^９、－ＳＲ^９、－Ｎ（Ｒ^１０）_２、－Ｓ（Ｏ）Ｒ^９、－Ｓ（Ｏ）_２Ｒ^９、－ＮＨＳ（Ｏ）_２Ｒ^９、－Ｓ（Ｏ）_２Ｎ（Ｒ^１０）_２、－Ｃ（Ｏ）Ｒ^９、－Ｃ（Ｏ）ＯＲ^１０、－ＯＣ（Ｏ）Ｒ^９、－Ｃ（Ｏ）Ｎ（Ｒ^１０）_２、－ＯＣ（Ｏ）Ｎ（Ｒ^１０）_２、－ＮＲ^１０Ｃ（Ｏ）Ｎ（Ｒ^１０）_２、－ＮＲ^１０Ｃ（Ｏ）Ｒ^９、－ＮＲ^１０Ｃ（Ｏ）ＯＲ^９、Ｃ_１－６アルキル、－Ｃ_１－６アルキル－ＯＨ、－Ｃ_１－６アルキル－ＯＲ^９、－Ｃ_１－６アルキル－Ｎ（Ｒ^１０）_２、Ｃ_２－６アルケニル、Ｃ_２－６アルキニル、Ｃ_１－６ハロアルキル、Ｃ_３－８シクロアルキル、および－Ｃ_１－６アルキル－Ｃ_３－８シクロアルキルから選択され；
Ｒ^５はそれぞれ独立して、ハロゲン、－ＣＮ、－ＯＨ、－ＯＲ^９、－ＳＲ^９、－Ｎ（Ｒ^１０）_２、－Ｓ（Ｏ）Ｒ^９、－Ｓ（Ｏ）_２Ｒ^９、－ＮＨＳ（Ｏ）_２Ｒ^９、－Ｓ（Ｏ）_２Ｎ（Ｒ^１０）_２、－Ｃ（Ｏ）ＮＨＳ（Ｏ）_２Ｎ（Ｒ^１０）_２、－Ｃ（Ｏ）Ｒ^９、－Ｃ（Ｏ）ＯＲ^１０、－ＯＣ（Ｏ）Ｒ^９、－Ｃ（Ｏ）Ｎ（Ｒ^１０）_２、－ＯＣ（Ｏ）Ｎ（Ｒ^１０）_２、－ＮＲ^１０Ｃ（Ｏ）Ｎ（Ｒ^１０）_２、－ＮＲ^１０Ｃ（Ｏ）Ｒ^９、－ＮＲ^１０Ｃ（Ｏ）ＯＲ^９、Ｃ_１－６アルキル、－Ｃ_１－６アルキル－ＯＨ、－Ｃ_１－６アルキル－ＯＲ^９、－Ｃ_１－６アルキル－Ｎ（Ｒ^１０）_２、－Ｃ_１－６アルキル－Ｃ（Ｏ）ＯＲ^１０、Ｃ_２－６アルケニル、Ｃ_２－６アルキニル、Ｃ_１－６ハロアルキル、Ｃ_１－６ハロアルキル－ＯＨ、Ｃ_３－８シクロアルキル、－Ｃ_１－６アルキル－Ｃ_３－８シクロアルキル、フェニル、－Ｃ_１－６アルキル－フェニル、Ｃ_２－９ヘテロシクロアルキル、およびＣ_１－９ヘテロアリールから選択され；ここで、フェニル、－Ｃ_１－６アルキル－フェニル、およびＣ_１－９ヘテロアリールは、ハロゲン、Ｃ_１－６アルキル、Ｃ_１－６ハロアルキル、Ｃ_３－８シクロアルキル、およびＣ_２－９ヘテロシクロアルキルから独立して選択される１つ、２つ、または３つの基で随意に置換され；ならびにここで、Ｃ_２－９ヘテロシクロアルキルは、ハロゲン、Ｃ_１－６アルキル、Ｃ_１－６ハロアルキル、およびオキソから独立して選択される１つ、２つ、または３つの基で随意に置換され；
Ｒ^９はそれぞれ独立して、Ｃ_１－６アルキル、Ｃ_１－６ハロアルキル、Ｃ_３－８シクロアルキル、－Ｃ_１－６アルキル－Ｃ_３－８シクロアルキル、フェニル、－Ｃ_１－６アルキル－フェニル、Ｃ_２－９ヘテロシクロアルキル、－Ｃ_１－６アルキル－Ｃ_２－９ヘテロシクロアルキル、Ｃ_２－９ヘテロアリール、および－Ｃ_１－６アルキル－Ｃ_２－９ヘテロアリールから選択され、ここで、Ｃ_１－６アルキル、フェニル、－Ｃ_１－６アルキル－フェニル、－Ｃ_１－６アルキル－Ｃ_２－９ヘテロシクロアルキル、Ｃ_２－９ヘテロアリール、および－Ｃ_１－６アルキル－Ｃ_２－９ヘテロアリールは、Ｃ_１－６アルキル、－ＯＲ１１、－Ｎ（Ｒ^１１）_２、Ｃ_１－６アルキル、Ｃ_３－８シクロアルキル、－Ｃ（Ｏ）Ｒ^１２、および－Ｃ（Ｏ）ＯＲ^１２から独立して選択される１つまたは２つの基で随意に置換され；
Ｒ^１０はそれぞれ独立して、Ｈ、Ｃ_１－６アルキル、Ｃ_１－６ハロアルキル、Ｃ_３－８シクロアルキル、－Ｃ_１－６アルキル－Ｃ_３－８シクロアルキル、フェニル、－Ｃ_１－６アルキル－フェニル、およびＣ_２－９ヘテロアリールから選択され、ここで、Ｃ_１－６アルキル、フェニル、－Ｃ_１－６アルキル－フェニル、およびＣ_２－９ヘテロアリールは、ハロゲン、Ｃ_１－６アルキル、－Ｎ（Ｒ^１１）_２、および－Ｃ（Ｏ）ＯＲ^１２から独立して選択される１つまたは２つの基で随意に置換され；あるいは、２つのＲ^１０、およびそれらが結合している窒素原子は一緒になって、Ｃ_１－６アルキル、オキソ、および－Ｃ（Ｏ）ＯＨから独立して選択される１つ、２つ、または３つの基で随意に置換された５員または６員のヘテロシクロアルキル環を形成し；
Ｒ^１１はそれぞれ独立して、ＨおよびＣ_１－６アルキルから選択され；
Ｒ^１２は独立して、ＨおよびＣ_１－６アルキルから選択され；
ｎは、０、１、２、または３であり；および、
ｐは、０、１、２、３、４、または５である。

During the ceremony
R ² is H, -OH, -N (R ¹⁰ ) ₂ , -NHS (O) ₂ R ⁹ , -S (O) ₂ N (R ¹⁰ ) ₂ , -C (O) N (R ¹⁰ ) ₂ , -OC (O) N (R ¹⁰ ) ₂ , -OC _1-6 alkyl, -C _1-6 alkyl-OH, -C _1-6 alkyl-OR ⁹ , -C _1-6 alkyl-N ( R ¹⁰ ) ₂ , C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _3-8 cycloalkyl;
R ³ are independently halogen, -CN, -OH, -OR ⁹ , -SR ⁹ , -N (R ¹⁰ ) ₂ , -S (O) R ⁹ , -S (O) ₂ R ⁹ ,- NHS (O) ₂ R ⁹ , -S (O) ₂ N (R ¹⁰ ) ₂ , -C (O) R ⁹ , -C (O) OR ¹⁰ , -OC (O) R ⁹ , -C (O) N (R ¹⁰ ) ₂ , -OC (O) N (R ¹⁰ ) ₂ , -NR ¹⁰ C (O) N (R ¹⁰ ) ₂ , -NR ¹⁰ C (O) R ⁹ , -NR ¹⁰ C (O) OR ⁹ , C _1-6 alkyl, -C _1-6 alkyl-OH, -C _1-6 alkyl-OR ⁹ , -C _1-6 alkyl-N (R ¹⁰ ) ₂ , C _2-6 alkenyl, C ₂ Selected from _-6 alkynyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, and -C _1-6 alkyl-C _3-8 cycloalkyl;
R ⁵ are independently halogen, -CN, -OH, -OR ⁹ , -SR ⁹ , -N (R ¹⁰ ) ₂ , -S (O) R ⁹ , -S (O) ₂ R ⁹ ,- NHS (O) ₂ R ⁹ , -S (O) ₂ N (R ¹⁰ ) ₂ , -C (O) NHS (O) ₂ N (R ¹⁰ ) ₂ , -C (O) R ⁹ , -C (O) ) OR ¹⁰ , -OC (O) R ⁹ , -C (O) N (R ¹⁰ ) ₂ , -OC (O) N (R ¹⁰ ) ₂ , -NR ¹⁰ C (O) N (R ¹⁰ ) ₂ , -NR ¹⁰ C (O) R ⁹ , -NR ¹⁰ C (O) OR ⁹ , C _1-6 alkyl, -C _1-6 alkyl-OH, -C _1-6 alkyl-OR ⁹ , -C _1-6 Alkyl-N (R ¹⁰ ) ₂ , -C _1-6 alkyl-C (O) OR ¹⁰ , C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _1-6 haloalkyl-OH, C Selected from _3-8 cycloalkyl, -C _1-6 alkyl-C _3-8 cycloalkyl, phenyl, -C _1-6 alkyl-phenyl, C _2-9 heterocycloalkyl, and C _1-9 heteroaryl; Here, phenyl, -C _1-6 alkyl-phenyl, and C _1-9 heteroaryl are halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, and C _2-9 hetero. It is optionally substituted with one, two, or three groups independently selected from cycloalkyl; and where C _2-9 heterocycloalkyl is halogen, C _1-6 alkyl, C _1-6 . Arbitrarily substituted with one, two, or three groups independently selected from haloalkyl, and oxo;
R ⁹ are independently C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, -C _1-6 alkyl-C _3-8 cycloalkyl, phenyl, -C _1-6 alkyl- Selected from phenyl, C _2-9 heterocycloalkyl, -C _1-6 alkyl-C _2-9 heterocycloalkyl, C _2-9 heteroaryl, and -C _1-6 alkyl-C _2-9 heteroaryl, Here, C _1-6 alkyl, phenyl, -C _1-6 alkyl-phenyl, -C _1-6 alkyl-C _2-9 heterocycloalkyl, C _2-9 heteroaryl, and -C _1-6 alkyl- C _2-9 heteroaryls are C _1-6 alkyl, -OR 11, -N (R ¹¹ ) ₂ , C _1-6 alkyl, C _3-8 cycloalkyl, -C (O) R ¹² , and -C ( O) Optionally substituted with one or two groups independently selected from OR ¹² ;
R ¹⁰ are independently H, C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, -C _1-6 alkyl-C _3-8 cycloalkyl, phenyl, -C _1-6 . Selected from alkyl-phenyl and C _2-9 heteroaryl, where C _1-6 alkyl, phenyl, -C _1-6 alkyl-phenyl, and C _2-9 heteroaryl are halogen, C _1-6 . It is optionally substituted with one or two groups independently selected from alkyl, -N (R ¹¹ ) ₂ , and -C (O) OR ¹² ; or two R ^10s , and they are combined. The nitrogen atoms present together are 5-membered or optionally substituted with one, two, or three groups independently selected from C _1-6 alkyl, oxo, and -C (O) OH. Forming a 6-membered heterocycloalkyl ring;
R ¹¹ is independently selected from H and C _1-6 alkyl;
^R12 is independently selected from H and C _1-6 alkyl;
n is 0, 1, 2, or 3; and
p is 0, 1, 2, 3, 4, or 5.

In some embodiments, there are compounds of formula (Ia), or pharmaceutically acceptable salts or solvates thereof, where p is 0, 1, or 2. In some embodiments, there is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, where p is 0. In some embodiments, there is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, where p is 1. In some embodiments, there is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, where p is 2. In some embodiments, there are compounds of formula (Ia), or pharmaceutically acceptable salts or solvates thereof, where p is 1 or 2. In some embodiments, there is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, where p is 1 or 2 and R ⁵ is independent of each other. Halogen, -OH, -OR ⁹ , -N (R ¹⁰ ) ₂ , -S (O) ₂ R ⁹ , -NHS (O) ₂ R ⁹ , -S (O) ₂ N (R ¹⁰ ) ₂ , -C (O) NHS (O) ₂ N (R ¹⁰ ) ₂ , -C (O) R ⁹ , -C (O) OR ¹⁰ , -OC (O) R ⁹ , -C (O) N (R ¹⁰ ) ₂ , -OC (O) N (R ¹⁰ ) ₂ , -NR ¹⁰ C (O) N (R ¹⁰ ) ₂ , -NR ¹⁰ C (O) R ⁹ , C _1-6 alkyl, -C _1-6 alkyl- OH, -C _1-6 alkyl-OR ⁹ , -C _1-6 alkyl-N (R ¹⁰ ) ₂ , -C _1-6 alkyl-C (O) OR ¹⁰ , C _1-6 haloalkyl, C _1-6 It is selected from haloalkyl-OH, C _3-8 cycloalkyl, C _2-9 heterocycloalkyl, and C _1-9 heteroaryl. In some embodiments, there is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, where p is 1 or 2 and R ⁵ is independent of each other. Halogen, -OH, -OR ⁹ , -N (R ¹⁰ ) ₂ , -S (O) ₂ R ⁹ , -NHS (O) ₂ R ⁹ , -S (O) ₂ N (R ¹⁰ ) ₂ , -C (O) NHS (O) ₂ N (R ¹⁰ ) ₂ , -C (O) R ⁹ , -C (O) OR ¹⁰ , -OC (O) R ⁹ , -C (O) N (R ¹⁰ ) ₂ , -OC (O) N (R ¹⁰ ) ₂ , -NR ¹⁰ C (O) N (R ¹⁰ ) ₂ , -NR ¹⁰ C (O) R ⁹ , C _1-6 alkyl, -C _1-6 alkyl- OH, -C _1-6 alkyl-OR ⁹ , -C _1-6 alkyl-N (R ¹⁰ ) ₂ , -C _1-6 alkyl-C (O) OR ¹⁰ , C _1-6 haloalkyl, C _1-6 Selected from haloalkyl-OH, C _3-8 cycloalkyl, C _2-9 heterocycloalkyl, and C _1-9 heteroaryl, R ¹⁰ is independently selected from H and C _1-6 alkyl, respectively. In some embodiments, there is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, where p is 1 or 2 and R ⁵ is independent of each other. Halogen, -OH, -OR ⁹ , -N (R ¹⁰ ) ₂ , -C (O) NHS (O) ₂ N (R ¹⁰ ) ₂ , -C (O) OR ¹⁰ , -C (O) N (R) ¹⁰ ) ₂ , -NR ¹⁰ C (O) R ⁹ , C _1-6 alkyl, -C _1-6 alkyl-C (O) OR ¹⁰ , and C _1-9 heteroaryl. In some embodiments, there is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, where p is 1 or 2 and R ⁵ is independent of each other. Halogen, -OH, -OR ⁹ , -N (R ¹⁰ ) ₂ , -C (O) NHS (O) ₂ N (R ¹⁰ ) ₂ , -C (O) OR ¹⁰ , -C (O) N (R) ¹⁰ ) ₂ , -NR ¹⁰ C (O) R ⁹ , C _1-6 alkyl, -C _1-6 alkyl-C (O) OR ¹⁰ , and C _1-9 heteroaryl, each R ¹⁰ independent Then, it is selected from H and C _1-6 alkyl. In some embodiments, there is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, where p is 1 or 2 and R ⁵ is independent of each other. -OR ⁹ , -C (O) OR ¹⁰ , -C (O) N (R ¹⁰ ) ₂ , C _1-6 alkyl, -C _1-6 alkyl-C (O) OR ¹⁰ are selected. In some embodiments, there is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, where p is 1 or 2 and R ⁵ is independent of each other. -OR ⁹ , -C (O) OR ¹⁰ , -C (O) N (R ¹⁰ ) ₂ , C _1-6 alkyl, -C _1-6 alkyl-C (O) OR ¹⁰ selected from R ¹⁰ Independently selected from H and C _1-6 alkyl. In some embodiments, there is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 1 or 2 and R ⁵ is independent of each other. -Selected from C (O) OR ¹⁰ . In some embodiments, there is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 1 or 2 and R ⁵ is independent of each other. -Selected from C (O) OR ¹⁰ and R ¹⁰ independently selected from H and C _1-6 alkyl. In some embodiments, there are compounds of formula (Ia), or pharmaceutically acceptable salts or solvates thereof, wherein R ¹ is:

であり、ｐは、１または２であり、Ｒ^５はそれぞれ独立して、－ＯＨ、－ＯＲ^９、および－Ｃ_１－６アルキル－Ｃ（Ｏ）ＯＲ^１０から選択される。いくつかの実施形態では、式（Ｉａ）の化合物、またはその薬学的に許容可能な塩あるいは溶媒和物があり、ここで、Ｒ^１は、

, P is 1 or 2, and R ⁵ is independently selected from -OH, -OR ⁹ , and -C _1-6 alkyl-C (O) OR ¹⁰ . In some embodiments, there are compounds of formula (Ia), or pharmaceutically acceptable salts or solvates thereof, wherein R ¹ is:

であり、ｐは、１または２であり、Ｒ^５はそれぞれ独立して、－ＯＨ、－ＯＲ^９、および－Ｃ_１－６アルキル－Ｃ（Ｏ）ＯＲ^１０から選択され、Ｒ^９は、－Ｃ（Ｏ）ＯＲ^１２で随意に置換されたＣ_１－６アルキルである。いくつかの実施形態では、式（Ｉａ）の化合物、またはその薬学的に許容可能な塩あるいは溶媒和物があり、ここで、ｐは１であり、Ｒ^５は独立して、－Ｃ（Ｏ）ＯＨから選択される。

And p is 1 or 2, R ⁵ is independently selected from -OH, -OR ⁹ and -C _1-6 alkyl-C (O) OR ¹⁰ , and R ⁹ is-. It is a C _1-6 alkyl optionally substituted with C (O) OR ¹² . In some embodiments, there is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, where p is 1 and R ⁵ is independently -C (O). ) Selected from OH.

In some embodiments, there are compounds of formula (Ia), or pharmaceutically acceptable salts or solvates thereof, wherein R ² is H, —OH, —N (R ¹⁰ ) ₂ , Or -OC _1-6 alkyl. In some embodiments, there are compounds of formula (Ia), or pharmaceutically acceptable salts or solvates thereof, wherein R ² is —OC _1-6 alkyl. In some embodiments, there is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R ² is —OCH ₂ CH ₃ . In some embodiments, there is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R ² is H. In some embodiments, there is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R ² is —OH. In some embodiments, there is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R ² is −N (R ¹⁰ ) ₂ .

In some embodiments, there is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, where n is 0.

In some embodiments, there are compounds of formula (Ia) or pharmaceutically acceptable salts or solvates thereof, wherein n is 1, 2 or 3. In some embodiments, there is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, where n is 1, 2, or 3 and R ³ is independent of each other. Then, halogen, -CN, -OR ⁹ , -N (R ¹⁰ ) ₂ , -S (O) ₂ R ⁹ , -NHS (O) ₂ R ⁹ , -S (O) ₂ N (R ¹⁰ ) ₂ , -C (O) R ⁹ , -C (O) OR ¹⁰ , -OC (O) R ⁹ , -C (O) N (R ¹⁰ ) ₂ , -NR ¹⁰ C (O) N (R ¹⁰ ) ₂ , -NR ¹⁰ C (O) R ⁹ , C _1-6 alkyl, -C _1-6 alkyl-OH, -C _1-6 alkyl-OR ⁹ , -C _1-6 alkyl-N (R ¹⁰ ) ₂ , It is selected from C _1-6 haloalkyl, C _3-8 cycloalkyl, and -C _1-6 alkyl-C _3-8 cycloalkyl. In some embodiments, there is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, where n is 1, 2, or 3 and R ³ is independent of each other. Then, it is selected from halogen, -OR ⁹ , -N (R ¹⁰ ) ₂ , -C (O) OR ¹⁰ , -C (O) N (R ¹⁰ ) ₂ , and C _1-6 alkyl. In some embodiments, there is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, where n is 1, 2, or 3 and R ³ is independent of each other. It is then selected from halogens and C _1-6 alkyls. In some embodiments, there are compounds of formula (Ia), or pharmaceutically acceptable salts or solvates thereof, where n is 1. In some embodiments, there is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, where n is 1 and R ³ is halogen, —OH, —OR. It is selected from ⁹ , -N (R ¹⁰ ) ₂ , C _1-6 alkyl, -C _1-6 alkyl-OH, -C _1-6 alkyl-OR ⁹ , and C _1-6 haloalkyl. In some embodiments, there is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, where n is ¹ , R3 is halogen, ^—OR9 , and. It is selected from C _1-6 alkyl. In some embodiments, there is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, where n is ¹ , R3 is halogen, ^—OR9 , and. It is selected from C _1-6 alkyl. In some embodiments, there is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, where n is 1 and R ³ is −OR ⁹ . In some embodiments, there is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, where n is 1, R ³ is -OR ⁹ , and R ⁹ is. Is C _3-8 cycloalkyl. In some embodiments, there is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, where n is 1, R ³ is -OR ⁹ , and R ⁹ is. Is cyclopentyl.

In some embodiments, compounds of formula (Ib), or pharmaceutically acceptable salts or solvates thereof, are provided herein.

式中、
Ｒ^１は、１つ、２つ、または３つのＲ^８基で随意に置換された５員または６員のヘテロアリールであり；
Ｒ^２は、Ｈ、－ＯＨ、－Ｎ（Ｒ^１０）_２、－ＮＨＳ（Ｏ）_２Ｒ^９、－Ｓ（Ｏ）_２Ｎ（Ｒ^１０）_２、－Ｃ（Ｏ）Ｎ（Ｒ^１０）_２、－ＯＣ（Ｏ）Ｎ（Ｒ^１０）_２、－Ｏ－Ｃ_１－６アルキル、－Ｃ_１－６アルキル－ＯＨ、－Ｃ_１－６アルキル－ＯＲ^９、－Ｃ_１－６アルキル－Ｎ（Ｒ^１０）_２、Ｃ_２－６アルケニル、Ｃ_２－６アルキニル、Ｃ_１－６ハロアルキル、Ｃ_３－８シクロアルキルであり；
Ｒ^３はそれぞれ独立して、ハロゲン、－ＣＮ、－ＯＨ、－ＯＲ^９、－ＳＲ^９、－Ｎ（Ｒ^１０）_２、－Ｓ（Ｏ）Ｒ^９、－Ｓ（Ｏ）_２Ｒ^９、－ＮＨＳ（Ｏ）_２Ｒ^９、－Ｓ（Ｏ）_２Ｎ（Ｒ^１０）_２、－Ｃ（Ｏ）Ｒ^９、－Ｃ（Ｏ）ＯＲ^１０、－ＯＣ（Ｏ）Ｒ^９、－Ｃ（Ｏ）Ｎ（Ｒ^１０）_２、－ＯＣ（Ｏ）Ｎ（Ｒ^１０）_２、－ＮＲ^１０Ｃ（Ｏ）Ｎ（Ｒ^１０）_２、－ＮＲ^１０Ｃ（Ｏ）Ｒ^９、－ＮＲ^１０Ｃ（Ｏ）ＯＲ^９、Ｃ_１－６アルキル、－Ｃ_１－６アルキル－ＯＨ、－Ｃ_１－６アルキル－ＯＲ^９、－Ｃ_１－６アルキル－Ｎ（Ｒ^１０）_２、Ｃ_２－６アルケニル、Ｃ_２－６アルキニル、Ｃ_１－６ハロアルキル、Ｃ_３－８シクロアルキル、および－Ｃ_１－６アルキル－Ｃ_３－８シクロアルキルから選択され；
Ｒ^８はそれぞれ独立して、ハロゲン、－ＯＨ、－ＯＲ^９、－Ｎ（Ｒ^１０）_２、－Ｓ（Ｏ）Ｒ^９、－Ｓ（Ｏ）_２Ｒ^９、－ＮＨＳ（Ｏ）_２Ｒ^９、－Ｓ（Ｏ）_２Ｎ（Ｒ^１０）_２、－Ｃ（Ｏ）ＮＨＳ（Ｏ）_２Ｎ（Ｒ^１０）_２、－Ｃ（Ｏ）Ｒ^９、－Ｃ（Ｏ）ＯＲ^１０、－ＯＣ（Ｏ）Ｒ^９、－Ｃ（Ｏ）Ｎ（Ｒ^１０）_２、－ＯＣ（Ｏ）Ｎ（Ｒ^１０）_２、－ＮＲ^１０Ｃ（Ｏ）Ｎ（Ｒ^１０）_２、－ＮＲ^１０Ｃ（Ｏ）Ｒ^９、－ＮＲ^１０Ｃ（Ｏ）ＯＲ^９、Ｃ_１－６アルキル、－Ｃ_１－６アルキル－ＯＨ、－Ｃ_１－６アルキル－ＯＲ^９、－Ｃ_１－６アルキル－Ｎ（Ｒ^１０）_２、－Ｃ_１－６アルキル－Ｃ（Ｏ）ＯＲ^１０、Ｃ_１－６ハロアルキル、Ｃ_１－６ハロアルキル－ＯＨ、Ｃ_３－８シクロアルキル、－Ｃ_１－６アルキル－Ｃ_３－８シクロアルキル、フェニル、－Ｃ_１－６アルキル－フェニル、Ｃ_２－９ヘテロシクロアルキル、およびＣ_１－９ヘテロアリールから選択され；ここで、フェニル、－Ｃ_１－６アルキル－フェニル、およびＣ_１－９ヘテロアリールは、ハロゲン、Ｃ_１－６アルキル、Ｃ_１－６ハロアルキル、Ｃ_３－８シクロアルキル、およびＣ_２－９ヘテロシクロアルキルから独立して選択される１つ、２つ、または３つの基で随意に置換され；ならびにここで、Ｃ_２－９ヘテロシクロアルキルは、ハロゲン、Ｃ_１－６アルキル、Ｃ_１－６ハロアルキル、およびオキソから独立して選択される１つ、２つ、または３つの基で随意に置換され；
Ｒ^９はそれぞれ独立して、Ｃ_１－６アルキル、Ｃ_１－６ハロアルキル、Ｃ_３－８シクロアルキル、－Ｃ_１－６アルキル－Ｃ_３－８シクロアルキル、フェニル、－Ｃ_１－６アルキル－フェニル、Ｃ_２－９ヘテロシクロアルキル、－Ｃ_１－６アルキル－Ｃ_２－９ヘテロシクロアルキル、Ｃ_２－９ヘテロアリール、および－Ｃ_１－６アルキル－Ｃ_２－９ヘテロアリールから選択され、ここで、Ｃ_１－６アルキル、フェニル、－Ｃ_１－６アルキル－フェニル、－Ｃ_１－６アルキル－Ｃ_２－９ヘテロシクロアルキル、Ｃ_２－９ヘテロアリール、および－Ｃ_１－６アルキル－Ｃ_２－９ヘテロアリールは、Ｃ_１－６アルキル、－ＯＲ１１、－Ｎ（Ｒ^１１）_２、Ｃ_１－６アルキル、Ｃ_３－８シクロアルキル、－Ｃ（Ｏ）Ｒ^１２、および－Ｃ（Ｏ）ＯＲ^１２から独立して選択される１つまたは２つの基で随意に置換され；
Ｒ^１０はそれぞれ独立して、Ｈ、Ｃ_１－６アルキル、Ｃ_１－６ハロアルキル、Ｃ_３－８シクロアルキル、－Ｃ_１－６アルキル－Ｃ_３－８シクロアルキル、フェニル、－Ｃ_１－６アルキル－フェニル、およびＣ_２－９ヘテロアリールから選択され、ここで、Ｃ_１－６アルキル、フェニル、－Ｃ_１－６アルキル－フェニル、およびＣ_２－９ヘテロアリールは、ハロゲン、Ｃ_１－６アルキル、－Ｎ（Ｒ^１１）_２、および－Ｃ（Ｏ）ＯＲ^１２から独立して選択される１つまたは２つの基で随意に置換され；あるいは、２つのＲ^１０、およびそれらが結合している窒素原子は一緒になって、Ｃ_１－６アルキル、オキソ、および－Ｃ（Ｏ）ＯＨから独立して選択される１つ、２つ、または３つの基で随意に置換された５員または６員のヘテロシクロアルキル環を形成し；
Ｒ^１１はそれぞれ独立して、ＨおよびＣ_１－６アルキルから選択され；
Ｒ^１２は独立して、ＨおよびＣ_１－６アルキルから選択され；および、
ｎは、０、１、２、または３である。

During the ceremony
^R1 is a 5- or ⁶ -membered heteroaryl optionally substituted with one, two, or three R8 groups;
R ² is H, -OH, -N (R ¹⁰ ) ₂ , -NHS (O) ₂ R ⁹ , -S (O) ₂ N (R ¹⁰ ) ₂ , -C (O) N (R ¹⁰ ) ₂ , -OC (O) N (R ¹⁰ ) ₂ , -OC _1-6 alkyl, -C _1-6 alkyl-OH, -C _1-6 alkyl-OR ⁹ , -C _1-6 alkyl-N ( R ¹⁰ ) ₂ , C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _3-8 cycloalkyl;
R ³ are independently halogen, -CN, -OH, -OR ⁹ , -SR ⁹ , -N (R ¹⁰ ) ₂ , -S (O) R ⁹ , -S (O) ₂ R ⁹ ,- NHS (O) ₂ R ⁹ , -S (O) ₂ N (R ¹⁰ ) ₂ , -C (O) R ⁹ , -C (O) OR ¹⁰ , -OC (O) R ⁹ , -C (O) N (R ¹⁰ ) ₂ , -OC (O) N (R ¹⁰ ) ₂ , -NR ¹⁰ C (O) N (R ¹⁰ ) ₂ , -NR ¹⁰ C (O) R ⁹ , -NR ¹⁰ C (O) OR ⁹ , C _1-6 alkyl, -C _1-6 alkyl-OH, -C _1-6 alkyl-OR ⁹ , -C _1-6 alkyl-N (R ¹⁰ ) ₂ , C _2-6 alkenyl, C ₂ Selected from _-6 alkynyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, and -C _1-6 alkyl-C _3-8 cycloalkyl;
R ⁸ are independently halogen, -OH, -OR ⁹ , -N (R ¹⁰ ) ₂ , -S (O) R ⁹ , -S (O) ₂ R ⁹ , -NHS (O) ₂ R ⁹ , -S (O) ₂ N (R ¹⁰ ) ₂ , -C (O) NHS (O) ₂ N (R ¹⁰ ) ₂ , -C (O) R ⁹ , -C (O) OR ¹⁰ , -OC ( O) R ⁹ , -C (O) N (R ¹⁰ ) ₂ , -OC (O) N (R ¹⁰ ) ₂ , -NR ¹⁰ C (O) N (R ¹⁰ ) ₂ , -NR ¹⁰ C (O) R ⁹ , -NR ¹⁰ C (O) OR ⁹ , C _1-6 alkyl, -C _1-6 alkyl-OH, -C _1-6 alkyl-OR ⁹ , -C _1-6 alkyl-N (R ¹⁰ ) ₂ , -C _1-6 alkyl-C (O) OR ¹⁰ , C _1-6 haloalkyl, C _1-6 haloalkyl-OH, C _3-8 cycloalkyl, -C _1-6 alkyl-C _3-8 cycloalkyl , Phenyl, -C _1-6 alkyl-phenyl, C _2-9 heterocycloalkyl, and C _1-9 heteroaryl; where phenyl, -C _1-6 alkyl-phenyl, and C _1-9 Heteroaryl is one, two or three groups independently selected from halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, and C _2-9 heterocycloalkyl. And where C _2-9 heterocycloalkyl is selected independently of halogen, C _1-6 alkyl, C _1-6 haloalkyl, and oxo, one, two, or three. Arbitrarily replaced by one group;
R ⁹ are independently C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, -C _1-6 alkyl-C _3-8 cycloalkyl, phenyl, -C _1-6 alkyl- Selected from phenyl, C _2-9 heterocycloalkyl, -C _1-6 alkyl-C _2-9 heterocycloalkyl, C _2-9 heteroaryl, and -C _1-6 alkyl-C _2-9 heteroaryl, Here, C _1-6 alkyl, phenyl, -C _1-6 alkyl-phenyl, -C _1-6 alkyl-C _2-9 heterocycloalkyl, C _2-9 heteroaryl, and -C _1-6 alkyl- C _2-9 heteroaryls are C _1-6 alkyl, -OR 11, -N (R ¹¹ ) ₂ , C _1-6 alkyl, C _3-8 cycloalkyl, -C (O) R ¹² , and -C ( O) Optionally substituted with one or two groups independently selected from OR ¹² ;
R ¹⁰ are independently H, C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, -C _1-6 alkyl-C _3-8 cycloalkyl, phenyl, -C _1-6 . Selected from alkyl-phenyl and C _2-9 heteroaryl, where C _1-6 alkyl, phenyl, -C _1-6 alkyl-phenyl, and C _2-9 heteroaryl are halogen, C _1-6 . It is optionally substituted with one or two groups independently selected from alkyl, -N (R ¹¹ ) ₂ , and -C (O) OR ¹² ; or two R ^10s , and they are combined. The nitrogen atoms present together are 5-membered or optionally substituted with one, two, or three groups independently selected from C _1-6 alkyl, oxo, and -C (O) OH. Forming a 6-membered heterocycloalkyl ring;
R ¹¹ is independently selected from H and C _1-6 alkyl;
^R12 is independently selected from H and C _1-6 alkyl; and
n is 0, 1, 2, or 3.

In some embodiments, there is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is 1, 2, or 3 R ⁸ groups. It is a 5-membered heteroaryl optionally substituted. In some embodiments, there is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is 1, 2, or 3 R ⁸ groups. Optionally substituted 5-membered heteroaryls, wherein the 5-membered heteroaryls are from oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, and thiadiazolyl. Be selected. In some embodiments, there is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is optionally substituted with one or two R ⁸ groups. It is a 5-membered heteroaryl, wherein the 5-membered heteroaryl is selected from oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, tetrazolyl, and isoxazolyl. In some embodiments, there is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is optionally substituted with one or two R ⁸ groups. It is oxazolyl. In some embodiments, there is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is optionally substituted with one or two R ⁸ groups. It is a thiazolyl. In some embodiments, there is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is optionally substituted with one or two R ⁸ groups. It is a pyrazolyl. In some embodiments, there is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is optionally substituted with one or two R ⁸ groups. It is a solvent. In some embodiments, there is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is optionally substituted with one or two R ⁸ groups. It is a solvation. In some embodiments, there is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is optionally substituted with one or two R ⁸ groups. It is a solvent. In some embodiments, there is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is optionally substituted with one or two R ⁸ groups. It is tetrazolyl. In some embodiments, there is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is optionally substituted with one or two R ⁸ groups. Isoxazolyl. In some embodiments, there is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is 1, 2, or 3 R ⁸ groups. It is a 6-membered heteroaryl optionally substituted. In some embodiments, there is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is 1, 2, or 3 R ⁸ groups. It is a optionally substituted 6-membered heteroaryl, wherein the 6-membered heteroaryl is selected from pyridinyl, pyrimidinyl, pyrazinyl, pyridadinyl, and triazineyl. In some embodiments, there is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is optionally substituted with one or two R ⁸ groups. 6-membered heteroaryl, where the 6-membered heteroaryl is selected from pyridinyl and pyrimidinyl. In some embodiments, there is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is optionally substituted with one or two R ⁸ groups. It is a pyridinyl. In some embodiments, there is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is optionally substituted with one or two R ⁸ groups. It is pyrimidinyl. In some embodiments, there are compounds of formula (Ib), or pharmaceutically acceptable salts or solvates thereof, wherein R ⁸ is independently halogen, —C (O) OR ¹⁰ . , C _1-6 alkyl, and -C _1-6 alkyl-C (O) OR ¹⁰ . In some embodiments, there are compounds of formula (Ib), or pharmaceutically acceptable salts or solvates thereof, wherein each R ⁸ is independently selected from -C (O) OR ¹⁰ . Will be done. In some embodiments, there are compounds of formula (Ib), or pharmaceutically acceptable salts or solvates thereof, wherein R ¹ is oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, tetrazolyl. , And an unsubstituted 5-membered heteroaryl selected from isoxazolyl. In some embodiments, there is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is an unsubstituted 6 member selected from pyridinyl and pyrimidinyl. Heteroaryl.

In some embodiments, there are compounds of formula (Ib), or pharmaceutically acceptable salts or solvates thereof, wherein R ² is H, —OH, —N (R ¹⁰ ) ₂ , ,. Or -OC _1-6 alkyl. In some embodiments, there are compounds of formula (Ib), or pharmaceutically acceptable salts or solvates thereof, wherein R ² is —OC _1-6 alkyl. In some embodiments, there is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R ² is —OCH ₂ CH ₃ . In some embodiments, there is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R ² is H. In some embodiments, there is a compound of formula (Ib), or a pharmaceutically acceptable salt or admixture thereof, wherein R ² is —OH. In some embodiments, there is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R ² is −N (R ¹⁰ ) ₂ .

In some embodiments, there is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, where n is 0.

In some embodiments, there are compounds of formula (Ib), or pharmaceutically acceptable salts or solvates thereof, where n is 1, 2, or 3. In some embodiments, there is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, where n is 1, 2, or 3 and R ³ is independent of each other. Then, halogen, -CN, -OR ⁹ , -N (R ¹⁰ ) ₂ , -S (O) ₂ R ⁹ , -NHS (O) ₂ R ⁹ , -S (O) ₂ N (R ¹⁰ ) ₂ , -C (O) R ⁹ , -C (O) OR ¹⁰ , -OC (O) R ⁹ , -C (O) N (R ¹⁰ ) ₂ , -NR ¹⁰ C (O) N (R ¹⁰ ) ₂ , -NR ¹⁰ C (O) R ⁹ , C _1-6 alkyl, -C _1-6 alkyl-OH, -C _1-6 alkyl-OR ⁹ , -C _1-6 alkyl-N (R ¹⁰ ) ₂ , It is selected from C _1-6 haloalkyl, C _3-8 cycloalkyl, and -C _1-6 alkyl-C _3-8 cycloalkyl. In some embodiments, there is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, where n is 1, 2, or 3 and R ³ is independent of each other. Then, it is selected from halogen, -OR ⁹ , -N (R ¹⁰ ) ₂ , -C (O) OR ¹⁰ , -C (O) N (R ¹⁰ ) ₂ , and C _1-6 alkyl. In some embodiments, there is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, where n is 1, 2, or 3 and R ³ is independent of each other. It is then selected from halogens and C _1-6 alkyls. In some embodiments, there is a compound of formula (Ib) or a pharmaceutically acceptable salt or solvate thereof, where n is 1. In some embodiments, there is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, where n is 1 and R ³ is halogen, —OH, —OR. It is selected from ⁹ , -N (R ¹⁰ ) ₂ , C _1-6 alkyl, -C _1-6 alkyl-OH, -C _1-6 alkyl-OR ⁹ , and C _1-6 haloalkyl. In some embodiments, there is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, where n is 1 and R ³ is a halogen, —OR ⁹ and. It is selected from C _1-6 alkyl. In some embodiments, there is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, where n is 1 and R ³ is a halogen, —OR ⁹ and. It is selected from C _1-6 alkyl. In some embodiments, there is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, where n is 1 and R ³ is −OR ⁹ . In some embodiments, there is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, where n is 1, R ³ is -OR ⁹ , and R ⁹ is. Is C _3-8 cycloalkyl. In some embodiments, there is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, where n is 1, R ³ is -OR ⁹ , and R ⁹ is. Is cyclopentyl.

In some embodiments, compounds of formula (Ic), or pharmaceutically acceptable salts or solvates thereof, are provided herein.

式中、
Ｒ^１は－Ｃ（Ｏ）Ｎ（Ｒ^１０）_２であり；
Ｒ^２は、Ｈ、－ＯＨ、－Ｎ（Ｒ^１０）_２、－ＮＨＳ（Ｏ）_２Ｒ^９、－Ｓ（Ｏ）_２Ｎ（Ｒ^１０）_２、－Ｃ（Ｏ）Ｎ（Ｒ^１０）_２、－ＯＣ（Ｏ）Ｎ（Ｒ^１０）_２、－Ｏ－Ｃ_１－６アルキル、－Ｃ_１－６アルキル－ＯＨ、－Ｃ_１－６アルキル－ＯＲ^９、－Ｃ_１－６アルキル－Ｎ（Ｒ^１０）_２、Ｃ_２－６アルケニル、Ｃ_２－６アルキニル、Ｃ_１－６ハロアルキル、Ｃ_３－８シクロアルキルであり；
Ｒ^３はそれぞれ独立して、ハロゲン、－ＣＮ、－ＯＨ、－ＯＲ^９、－ＳＲ^９、－Ｎ（Ｒ^１０）_２、－Ｓ（Ｏ）Ｒ^９、－Ｓ（Ｏ）_２Ｒ^９、－ＮＨＳ（Ｏ）_２Ｒ^９、－Ｓ（Ｏ）_２Ｎ（Ｒ^１０）_２、－Ｃ（Ｏ）Ｒ^９、－Ｃ（Ｏ）ＯＲ^１０、－ＯＣ（Ｏ）Ｒ^９、－Ｃ（Ｏ）Ｎ（Ｒ^１０）_２、－ＯＣ（Ｏ）Ｎ（Ｒ^１０）_２、－ＮＲ^１０Ｃ（Ｏ）Ｎ（Ｒ^１０）_２、－ＮＲ^１０Ｃ（Ｏ）Ｒ^９、－ＮＲ^１０Ｃ（Ｏ）ＯＲ^９、Ｃ_１－６アルキル、－Ｃ_１－６アルキル－ＯＨ、－Ｃ_１－６アルキル－ＯＲ^９、－Ｃ_１－６アルキル－Ｎ（Ｒ^１０）_２、Ｃ_２－６アルケニル、Ｃ_２－６アルキニル、Ｃ_１－６ハロアルキル、Ｃ_３－８シクロアルキル、および－Ｃ_１－６アルキル－Ｃ_３－８シクロアルキルから選択され；
Ｒ^９はそれぞれ独立して、Ｃ_１－６アルキル、Ｃ_１－６ハロアルキル、Ｃ_３－８シクロアルキル、－Ｃ_１－６アルキル－Ｃ_３－８シクロアルキル、フェニル、－Ｃ_１－６アルキル－フェニル、Ｃ_２－９ヘテロシクロアルキル、－Ｃ_１－６アルキル－Ｃ_２－９ヘテロシクロアルキル、Ｃ_２－９ヘテロアリール、および－Ｃ_１－６アルキル－Ｃ_２－９ヘテロアリールから選択され、ここで、Ｃ_１－６アルキル、フェニル、－Ｃ_１－６アルキル－フェニル、－Ｃ_１－６アルキル－Ｃ_２－９ヘテロシクロアルキル、Ｃ_２－９ヘテロアリール、および－Ｃ_１－６アルキル－Ｃ_２－９ヘテロアリールは、Ｃ_１－６アルキル、－ＯＲ１１、－Ｎ（Ｒ^１１）_２、Ｃ_１－６アルキル、Ｃ_３－８シクロアルキル、－Ｃ（Ｏ）Ｒ^１２、および－Ｃ（Ｏ）ＯＲ^１２から独立して選択される１つまたは２つの基で随意に置換され；
Ｒ^１０はそれぞれ独立して、Ｈ、Ｃ_１－６アルキル、Ｃ_１－６ハロアルキル、Ｃ_３－８シクロアルキル、－Ｃ_１－６アルキル－Ｃ_３－８シクロアルキル、フェニル、－Ｃ_１－６アルキル－フェニル、およびＣ_２－９ヘテロアリールから選択され、ここで、Ｃ_１－６アルキル、フェニル、－Ｃ_１－６アルキル－フェニル、およびＣ_２－９ヘテロアリールは、ハロゲン、Ｃ_１－６アルキル、－Ｎ（Ｒ^１１）_２、および－Ｃ（Ｏ）ＯＲ^１２から独立して選択される１つまたは２つの基で随意に置換され；あるいは、２つのＲ^１０、およびそれらが結合している窒素原子は一緒になって、Ｃ_１－６アルキル、オキソ、および－Ｃ（Ｏ）ＯＨから独立して選択される１つ、２つ、または３つの基で随意に置換された５員または６員のヘテロシクロアルキル環を形成し；
Ｒ^１１はそれぞれ独立して、ＨおよびＣ_１－６アルキルから選択され；
Ｒ^１２は独立して、ＨおよびＣ_１－６アルキルから選択され；および、
ｎは、０、１、２、または３である。

During the ceremony
R ¹ is -C (O) N (R ¹⁰ ) ₂ ;
R ² is H, -OH, -N (R ¹⁰ ) ₂ , -NHS (O) ₂ R ⁹ , -S (O) ₂ N (R ¹⁰ ) ₂ , -C (O) N (R ¹⁰ ) ₂ , -OC (O) N (R ¹⁰ ) ₂ , -OC _1-6 alkyl, -C _1-6 alkyl-OH, -C _1-6 alkyl-OR ⁹ , -C _1-6 alkyl-N ( R ¹⁰ ) ₂ , C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _3-8 cycloalkyl;
R ³ are independently halogen, -CN, -OH, -OR ⁹ , -SR ⁹ , -N (R ¹⁰ ) ₂ , -S (O) R ⁹ , -S (O) ₂ R ⁹ ,- NHS (O) ₂ R ⁹ , -S (O) ₂ N (R ¹⁰ ) ₂ , -C (O) R ⁹ , -C (O) OR ¹⁰ , -OC (O) R ⁹ , -C (O) N (R ¹⁰ ) ₂ , -OC (O) N (R ¹⁰ ) ₂ , -NR ¹⁰ C (O) N (R ¹⁰ ) ₂ , -NR ¹⁰ C (O) R ⁹ , -NR ¹⁰ C (O) OR ⁹ , C _1-6 alkyl, -C _1-6 alkyl-OH, -C _1-6 alkyl-OR ⁹ , -C _1-6 alkyl-N (R ¹⁰ ) ₂ , C _2-6 alkenyl, C ₂ Selected from _-6 alkynyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, and -C _1-6 alkyl-C _3-8 cycloalkyl;
R ⁹ are independently C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, -C _1-6 alkyl-C _3-8 cycloalkyl, phenyl, -C _1-6 alkyl- Selected from phenyl, C _2-9 heterocycloalkyl, -C _1-6 alkyl-C _2-9 heterocycloalkyl, C _2-9 heteroaryl, and -C _1-6 alkyl-C _2-9 heteroaryl, Here, C _1-6 alkyl, phenyl, -C _1-6 alkyl-phenyl, -C _1-6 alkyl-C _2-9 heterocycloalkyl, C _2-9 heteroaryl, and -C _1-6 alkyl- C _2-9 heteroaryls are C _1-6 alkyl, -OR 11, -N (R ¹¹ ) ₂ , C _1-6 alkyl, C _3-8 cycloalkyl, -C (O) R ¹² , and -C ( O) Optionally substituted with one or two groups independently selected from OR ¹² ;
R ¹⁰ are independently H, C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, -C _1-6 alkyl-C _3-8 cycloalkyl, phenyl, -C _1-6 . Selected from alkyl-phenyl and C _2-9 heteroaryl, where C _1-6 alkyl, phenyl, -C _1-6 alkyl-phenyl, and C _2-9 heteroaryl are halogen, C _1-6 . It is optionally substituted with one or two groups independently selected from alkyl, -N (R ¹¹ ) ₂ , and -C (O) OR ¹² ; or two R ^10s , and they are combined. The nitrogen atoms present together are 5-membered or optionally substituted with one, two, or three groups independently selected from C _1-6 alkyl, oxo, and -C (O) OH. Forming a 6-membered heterocycloalkyl ring;
R ¹¹ is independently selected from H and C _1-6 alkyl;
^R12 is independently selected from H and C _1-6 alkyl; and
n is 0, 1, 2, or 3.

In some embodiments, there are compounds of formula (Ic), or pharmaceutically acceptable salts or solvates thereof, wherein R ¹⁰ is independently H, C _1-6 alkyl, C, respectively. Selected from _1-6 haloalkyl, C _3-8 cycloalkyl, -C _1-6 alkyl-C _3-8 cycloalkyl, phenyl, -C _1-6 alkyl-phenyl, and C _2-9 heteroaryl, where , C _1-6 alkyl, phenyl, -C _1-6 alkyl-phenyl, and C _2-9 heteroaryl are halogen, C _1-6 alkyl, -N (R ¹¹ ) ₂ , and -C (O) OR. It is optionally substituted with one or two groups independently selected from ^twelve . In some embodiments, there are compounds of formula (Ic), or pharmaceutically acceptable salts or solvates thereof, wherein R ¹⁰ is independently H, C _1-6 alkyl, C, respectively. Selected from _3-8 cycloalkyl, phenyl, and C _2-9 heteroaryl, where C _1-6 alkyl, phenyl, and C _2-9 heteroaryl are independently halogen, C _1-6 alkyl,. Substituted with one or two groups selected from -N (R ¹¹ ) ₂ and -C (O) OR ¹² . In some embodiments, there are compounds of formula (Ic), or pharmaceutically acceptable salts or solvates thereof, wherein R ¹⁰ are independently H, and —C (O) OR, respectively. It is selected from C _1-6 alkyl optionally substituted with ¹² . In some embodiments, there are compounds of formula (Ic), or pharmaceutically acceptable salts or solvates thereof, wherein R ¹⁰ are independently H, and —C (O) OH, respectively. It is selected from C _1-6 alkyl optionally substituted with. In some embodiments, there is a compound of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is -C (O) N (R ¹⁰ ) ₂ . The two ^R10s , and the nitrogen atom to which they are attached, together are one, two, or three groups independently selected from C _1-6 alkyl, oxo, and -C (O) OH. Form a 5- or 6-membered heterocycloalkyl ring optionally substituted with. In some embodiments, there is a compound of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is -C (O) N (R ¹⁰ ) ₂ . The two ^R10s , and the nitrogen atom to which they bind, together form a 5-membered heterocycloalkyl ring substituted with -C (O) OH. In some embodiments, there is a compound of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is -C (O) N (R ¹⁰ ) ₂ . The two ^R10s , and the nitrogen atom to which they bind, together form a 6-membered heterocycloalkyl ring substituted with -C (O) OH.

In some embodiments, there are compounds of formula (Ic), or pharmaceutically acceptable salts or solvates thereof, wherein R ² is H, —OH, —N (R ¹⁰ ) ₂ , Or -OC _1-6 alkyl. In some embodiments, there are compounds of formula (Ic), or pharmaceutically acceptable salts or solvates thereof, wherein R ² is —OC _1-6 alkyl. In some embodiments, there is a compound of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R ² is —OCH ₂ CH ₃ . In some embodiments, there is a compound of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R ² is H. In some embodiments, there are compounds of formula (Ic), or pharmaceutically acceptable salts or solvates thereof, wherein R ² is —OH. In some embodiments, there is a compound of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R ² is −N (R ¹⁰ ) ₂ .

In some embodiments, there is a compound of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, where n is 0.

In some embodiments, there are compounds of formula (Ic), or pharmaceutically acceptable salts or solvates thereof, where n is 1, 2, or 3. In some embodiments, there is a compound of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, where n is 1, 2, or 3 and R ³ is independent of each other. Then, halogen, -CN, -OR ⁹ , -N (R ¹⁰ ) ₂ , -S (O) ₂ R ⁹ , -NHS (O) ₂ R ⁹ , -S (O) ₂ N (R ¹⁰ ) ₂ , -C (O) R ⁹ , -C (O) OR ¹⁰ , -OC (O) R ⁹ , -C (O) N (R ¹⁰ ) ₂ , -NR ¹⁰ C (O) N (R ¹⁰ ) ₂ , -NR ¹⁰ C (O) R ⁹ , C _1-6 alkyl, -C _1-6 alkyl-OH, -C _1-6 alkyl-OR ⁹ , -C _1-6 alkyl-N (R ¹⁰ ) ₂ , It is selected from C _1-6 haloalkyl, C _3-8 cycloalkyl, and -C _1-6 alkyl-C _3-8 cycloalkyl. In some embodiments, there is a compound of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, where n is 1, 2, or 3 and R ³ is independent of each other. Then, it is selected from halogen, -OR ⁹ , -N (R ¹⁰ ) ₂ , -C (O) OR ¹⁰ , -C (O) N (R ¹⁰ ) ₂ , and C _1-6 alkyl. In some embodiments, there is a compound of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, where n is 1, 2, or 3 and R ³ is independent of each other. It is then selected from halogens and C _1-6 alkyls. In some embodiments, there are compounds of formula (Ic), or pharmaceutically acceptable salts or solvates thereof, where n is 1. In some embodiments, there is a compound of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, where n is 1 and R ³ is halogen, —OH, —OR. It is selected from ⁹ , -N (R ¹⁰ ) ₂ , C _1-6 alkyl, -C _1-6 alkyl-OH, -C _1-6 alkyl-OR ⁹ , and C _1-6 haloalkyl. In some embodiments, there is a compound of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, where n is ¹ , R3 is halogen, ^—OR9 , and. It is selected from C _1-6 alkyl. In some embodiments, there is a compound of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, where n is ¹ , R3 is halogen, ^—OR9 , and. It is selected from C _1-6 alkyl. In some embodiments, there is a compound of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, where n is 1 and R ³ is −OR ⁹ . In some embodiments, there is a compound of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, where n is 1, R ³ is -OR ⁹ , and R ⁹ is. Is C _3-8 cycloalkyl. In some embodiments, there is a compound of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, where n is 1, R ³ is -OR ⁹ , and R ⁹ is. Is cyclopentyl.

In some embodiments, compounds of formula (Id), or pharmaceutically acceptable salts or solvates thereof, are provided herein.

式中、
Ｒ^１は－Ｎ（Ｒ^１０）_２であり；
Ｒ^２は、Ｈ、－ＯＨ、－Ｎ（Ｒ^１０）_２、－ＮＨＳ（Ｏ）_２Ｒ^９、－Ｓ（Ｏ）_２Ｎ（Ｒ^１０）_２、－Ｃ（Ｏ）Ｎ（Ｒ^１０）_２、－ＯＣ（Ｏ）Ｎ（Ｒ^１０）_２、－Ｏ－Ｃ_１－６アルキル、－Ｃ_１－６アルキル－ＯＨ、－Ｃ_１－６アルキル－ＯＲ^９、－Ｃ_１－６アルキル－Ｎ（Ｒ^１０）_２、Ｃ_２－６アルケニル、Ｃ_２－６アルキニル、Ｃ_１－６ハロアルキル、Ｃ_３－８シクロアルキルであり；
Ｒ^３はそれぞれ独立して、ハロゲン、－ＣＮ、－ＯＨ、－ＯＲ^９、－ＳＲ^９、－Ｎ（Ｒ^１０）_２、－Ｓ（Ｏ）Ｒ^９、－Ｓ（Ｏ）_２Ｒ^９、－ＮＨＳ（Ｏ）_２Ｒ^９、－Ｓ（Ｏ）_２Ｎ（Ｒ^１０）_２、－Ｃ（Ｏ）Ｒ^９、－Ｃ（Ｏ）ＯＲ^１０、－ＯＣ（Ｏ）Ｒ^９、－Ｃ（Ｏ）Ｎ（Ｒ^１０）_２、－ＯＣ（Ｏ）Ｎ（Ｒ^１０）_２、－ＮＲ^１０Ｃ（Ｏ）Ｎ（Ｒ^１０）_２、－ＮＲ^１０Ｃ（Ｏ）Ｒ^９、－ＮＲ^１０Ｃ（Ｏ）ＯＲ^９、Ｃ_１－６アルキル、－Ｃ_１－６アルキル－ＯＨ、－Ｃ_１－６アルキル－ＯＲ^９、－Ｃ_１－６アルキル－Ｎ（Ｒ^１０）_２、Ｃ_２－６アルケニル、Ｃ_２－６アルキニル、Ｃ_１－６ハロアルキル、Ｃ_３－８シクロアルキル、および－Ｃ_１－６アルキル－Ｃ_３－８シクロアルキルから選択され；
Ｒ^９はそれぞれ独立して、Ｃ_１－６アルキル、Ｃ_１－６ハロアルキル、Ｃ_３－８シクロアルキル、－Ｃ_１－６アルキル－Ｃ_３－８シクロアルキル、フェニル、－Ｃ_１－６アルキル－フェニル、Ｃ_２－９ヘテロシクロアルキル、－Ｃ_１－６アルキル－Ｃ_２－９ヘテロシクロアルキル、Ｃ_２－９ヘテロアリール、および－Ｃ_１－６アルキル－Ｃ_２－９ヘテロアリールから選択され、ここで、Ｃ_１－６アルキル、フェニル、－Ｃ_１－６アルキル－フェニル、－Ｃ_１－６アルキル－Ｃ_２－９ヘテロシクロアルキル、Ｃ_２－９ヘテロアリール、および－Ｃ_１－６アルキル－Ｃ_２－９ヘテロアリールは、Ｃ_１－６アルキル、－ＯＲ１１、－Ｎ（Ｒ^１１）_２、Ｃ_１－６アルキル、Ｃ_３－８シクロアルキル、－Ｃ（Ｏ）Ｒ^１２、および－Ｃ（Ｏ）ＯＲ^１２から独立して選択される１つまたは２つの基で随意に置換され；
Ｒ^１０はそれぞれ独立して、Ｈ、Ｃ_１－６アルキル、Ｃ_１－６ハロアルキル、Ｃ_３－８シクロアルキル、－Ｃ_１－６アルキル－Ｃ_３－８シクロアルキル、フェニル、－Ｃ_１－６アルキル－フェニル、およびＣ_２－９ヘテロアリールから選択され、ここで、Ｃ_１－６アルキル、フェニル、－Ｃ_１－６アルキル－フェニル、およびＣ_２－９ヘテロアリールは、ハロゲン、Ｃ_１－６アルキル、－Ｎ（Ｒ^１１）_２、および－Ｃ（Ｏ）ＯＲ^１２から独立して選択される１つまたは２つの基で随意に置換され；あるいは、２つのＲ^１０、およびそれらが結合している窒素原子は一緒になって、Ｃ_１－６アルキル、オキソ、および－Ｃ（Ｏ）ＯＨから独立して選択される１つ、２つ、または３つの基で随意に置換された５員または６員のヘテロシクロアルキル環を形成し；
Ｒ^１１はそれぞれ独立して、ＨおよびＣ_１－６アルキルから選択され；
Ｒ^１２は独立して、ＨおよびＣ_１－６アルキルから選択され；および、
ｎは、０、１、２、または３である。

During the ceremony
R ¹ is -N (R ¹⁰ ) ₂ ;
R ² is H, -OH, -N (R ¹⁰ ) ₂ , -NHS (O) ₂ R ⁹ , -S (O) ₂ N (R ¹⁰ ) ₂ , -C (O) N (R ¹⁰ ) ₂ , -OC (O) N (R ¹⁰ ) ₂ , -OC _1-6 alkyl, -C _1-6 alkyl-OH, -C _1-6 alkyl-OR ⁹ , -C _1-6 alkyl-N ( R ¹⁰ ) ₂ , C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _3-8 cycloalkyl;
R ³ are independently halogen, -CN, -OH, -OR ⁹ , -SR ⁹ , -N (R ¹⁰ ) ₂ , -S (O) R ⁹ , -S (O) ₂ R ⁹ ,- NHS (O) ₂ R ⁹ , -S (O) ₂ N (R ¹⁰ ) ₂ , -C (O) R ⁹ , -C (O) OR ¹⁰ , -OC (O) R ⁹ , -C (O) N (R ¹⁰ ) ₂ , -OC (O) N (R ¹⁰ ) ₂ , -NR ¹⁰ C (O) N (R ¹⁰ ) ₂ , -NR ¹⁰ C (O) R ⁹ , -NR ¹⁰ C (O) OR ⁹ , C _1-6 alkyl, -C _1-6 alkyl-OH, -C _1-6 alkyl-OR ⁹ , -C _1-6 alkyl-N (R ¹⁰ ) ₂ , C _2-6 alkenyl, C ₂ Selected from _-6 alkynyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, and -C _1-6 alkyl-C _3-8 cycloalkyl;
R ⁹ are independently C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, -C _1-6 alkyl-C _3-8 cycloalkyl, phenyl, -C _1-6 alkyl- Selected from phenyl, C _2-9 heterocycloalkyl, -C _1-6 alkyl-C _2-9 heterocycloalkyl, C _2-9 heteroaryl, and -C _1-6 alkyl-C _2-9 heteroaryl, Here, C _1-6 alkyl, phenyl, -C _1-6 alkyl-phenyl, -C _1-6 alkyl-C _2-9 heterocycloalkyl, C _2-9 heteroaryl, and -C _1-6 alkyl- C _2-9 heteroaryls are C _1-6 alkyl, -OR 11, -N (R ¹¹ ) ₂ , C _1-6 alkyl, C _3-8 cycloalkyl, -C (O) R ¹² , and -C ( O) Optionally substituted with one or two groups independently selected from OR ¹² ;
R ¹⁰ are independently H, C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, -C _1-6 alkyl-C _3-8 cycloalkyl, phenyl, -C _1-6 . Selected from alkyl-phenyl and C _2-9 heteroaryl, where C _1-6 alkyl, phenyl, -C _1-6 alkyl-phenyl, and C _2-9 heteroaryl are halogen, C _1-6 . It is optionally substituted with one or two groups independently selected from alkyl, -N (R ¹¹ ) ₂ , and -C (O) OR ¹² ; or two R ^10s , and they are combined. The nitrogen atoms present together are 5-membered or optionally substituted with one, two, or three groups independently selected from C _1-6 alkyl, oxo, and -C (O) OH. Forming a 6-membered heterocycloalkyl ring;
R ¹¹ is independently selected from H and C _1-6 alkyl;
^R12 is independently selected from H and C _1-6 alkyl; and
n is 0, 1, 2, or 3.

In some embodiments, there is a compound of formula (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹⁰ is independently H, C _1-6 alkyl, C, respectively. Selected from _1-6 haloalkyl, C _3-8 cycloalkyl, -C _1-6 alkyl-C _3-8 cycloalkyl, phenyl, -C _1-6 alkyl-phenyl, and C _2-9 heteroaryl, where , C _1-6 alkyl, phenyl, -C _1-6 alkyl-phenyl, and C _2-9 heteroaryl are halogen, C _1-6 alkyl, -N (R ¹¹ ) ₂ , and -C (O) OR. It is optionally substituted with one or two groups independently selected from ^twelve . In some embodiments, there is a compound of formula (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹⁰ is independently H, C _1-6 alkyl, C, respectively. Selected from _3-8 cycloalkyl, phenyl, and C _2-9 heteroaryl, where C _1-6 alkyl, phenyl, and C _2-9 heteroaryl are independently halogen, C _1-6 alkyl,. Substituted with one or two groups selected from -N (R ¹¹ ) ₂ and -C (O) OR ¹² . In some embodiments, there are compounds of formula (Id), or pharmaceutically acceptable salts or solvates thereof, wherein R ¹⁰ are independently H, and —C (O) OR, respectively. It is selected from C _1-6 alkyl optionally substituted with ¹² . In some embodiments, there are compounds of formula (Id), or pharmaceutically acceptable salts or solvates thereof, wherein R ¹⁰ are independently H, and —C (O) OH, respectively. It is selected from C _1-6 alkyl optionally substituted with. In some embodiments, there is a compound of formula (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is -N (R ¹⁰ ) ₂ and two R ^10s . , And the nitrogen atoms to which they are attached are combined and optionally substituted with one, two, or three groups independently selected from C _1-6 alkyl, oxo, and -C (O) OH. Form a 5- or 6-membered heterocycloalkyl ring. In some embodiments, there is a compound of formula (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is -N (R ¹⁰ ) ₂ and two R ^10s . , And the nitrogen atoms to which they bind together form a 5-membered heterocycloalkyl ring substituted with —C (O) OH. In some embodiments, there is a compound of formula (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is -N (R ¹⁰ ) ₂ and two R ^10s . , And the nitrogen atoms to which they bind together form a 6-membered heterocycloalkyl ring substituted with —C (O) OH.

In some embodiments, there are compounds of formula (Id), or pharmaceutically acceptable salts or solvates thereof, wherein R ² is H, —OH, —N (R ¹⁰ ) ₂ , ,. Or -OC _1-6 alkyl. In some embodiments, there are compounds of formula (Id), or pharmaceutically acceptable salts or solvates thereof, wherein R ² is —OC _1-6 alkyl. In some embodiments, there is a compound of formula (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R ² is —OCH ₂ CH ₃ . In some embodiments, there is a compound of formula (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R ² is H. In some embodiments, there is a compound of formula (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R ² is —OH. In some embodiments, there is a compound of formula (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R ² is −N (R ¹⁰ ) ₂ .

In some embodiments, there is a compound of formula (Id), or a pharmaceutically acceptable salt or solvate thereof, where n is 0.

In some embodiments, there are compounds of formula (Id), or pharmaceutically acceptable salts or solvates thereof, where n is 1, 2, or 3. In some embodiments, there is a compound of formula (Id), or a pharmaceutically acceptable salt or solvate thereof, where n is 1, 2, or 3 and R ³ is independent of each other. Then, halogen, -CN, -OR ⁹ , -N (R ¹⁰ ) ₂ , -S (O) ₂ R ⁹ , -NHS (O) ₂ R ⁹ , -S (O) ₂ N (R ¹⁰ ) ₂ , -C (O) R ⁹ , -C (O) OR ¹⁰ , -OC (O) R ⁹ , -C (O) N (R ¹⁰ ) ₂ , -NR ¹⁰ C (O) N (R ¹⁰ ) ₂ , -NR ¹⁰ C (O) R ⁹ , C _1-6 alkyl, -C _1-6 alkyl-OH, -C _1-6 alkyl-OR ⁹ , -C _1-6 alkyl-N (R ¹⁰ ) ₂ , It is selected from C _1-6 haloalkyl, C _3-8 cycloalkyl, and -C _1-6 alkyl-C _3-8 cycloalkyl. In some embodiments, there is a compound of formula (Id), or a pharmaceutically acceptable salt or solvate thereof, where n is 1, 2, or 3 and R ³ is independent of each other. Then, it is selected from halogen, -OR ⁹ , -N (R ¹⁰ ) ₂ , -C (O) OR ¹⁰ , -C (O) N (R ¹⁰ ) ₂ , and C _1-6 alkyl. In some embodiments, there is a compound of formula (Id), or a pharmaceutically acceptable salt or solvate thereof, where n is 1, 2, or 3 and R ³ is independent of each other. It is then selected from halogens and C _1-6 alkyls. In some embodiments, there are compounds of formula (Id), or pharmaceutically acceptable salts or solvates thereof, where n is 1. In some embodiments, there is a compound of formula (Id), or a pharmaceutically acceptable salt or solvate thereof, where n is 1 and R ³ is halogen, —OH, —OR. It is selected from ⁹ , -N (R ¹⁰ ) ₂ , C _1-6 alkyl, -C _1-6 alkyl-OH, -C _1-6 alkyl-OR ⁹ , and C _1-6 haloalkyl. In some embodiments, there is a compound of formula (Id), or a pharmaceutically acceptable salt or solvate thereof, where n is ¹ , R3 is halogen, ^—OR9 , and. It is selected from C _1-6 alkyl. In some embodiments, there is a compound of formula (Id), or a pharmaceutically acceptable salt or solvate thereof, where n is ¹ , R3 is halogen, ^—OR9 , and. It is selected from C _1-6 alkyl. In some embodiments, there is a compound of formula (Id), or a pharmaceutically acceptable salt or solvate thereof, where n is 1 and R ³ is −OR ⁹ . In some embodiments, there is a compound of formula (Id), or a pharmaceutically acceptable salt or solvate thereof, where n is 1, R ³ is -OR ⁹ , and R ⁹ is. Is C _3-8 cycloalkyl. In some embodiments, there is a compound of formula (Id), or a pharmaceutically acceptable salt or solvate thereof, where n is 1, R ³ is -OR ⁹ , and R ⁹ is. Is cyclopentyl.

In some embodiments,

から選択される化合物、またはその薬学的に許容可能な塩あるいは溶媒和物が提供される。

Provided are compounds selected from, or pharmaceutically acceptable salts or solvates thereof.

In some embodiments,

から選択される化合物、またはその薬学的に許容可能な塩あるいは溶媒和物が提供される。

Provided are compounds selected from, or pharmaceutically acceptable salts or solvates thereof.

In some embodiments,

から選択される化合物、またはその薬学的に許容可能な塩あるいは溶媒和物が提供される。

Provided are compounds selected from, or pharmaceutically acceptable salts or solvates thereof.

In some embodiments,

から選択される化合物、またはその薬学的に許容可能な塩あるいは溶媒和物が提供される。

Provided are compounds selected from, or pharmaceutically acceptable salts or solvates thereof.

In some embodiments,

から選択される化合物、またはその薬学的に許容可能な塩あるいは溶媒和物が提供される。

Provided are compounds selected from, or pharmaceutically acceptable salts or solvates thereof.

In some embodiments,

から選択される化合物、またはその薬学的に許容可能な塩あるいは溶媒和物が提供される。

Provided are compounds selected from, or pharmaceutically acceptable salts or solvates thereof.

Any combination of the above groups of various variables is contemplated herein. Throughout the specification, groups and their substituents are selectable by one of ordinary skill in the art to provide stable moieties and compounds.

In some embodiments, the therapeutic agent (eg, a compound of formula (I), (I'), (I''), (Ia), (Ib), (Ic), or (Id)) is a pharmaceutical. It is present in the pharmaceutical composition as a reasonably acceptable salt. In some embodiments, the compounds described above are suitable for any method or composition described herein.

Further Morphological Isomers of Compounds Disclosed herein In addition, in some embodiments, the compounds described herein are present as geometric isomers. In some embodiments, the compounds described herein have one or more double bonds. The compounds presented in the present invention include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers, as well as their corresponding mixtures. In some situations, the compound exists as a tautomer. The compounds described herein include any tautomer possible in the formulas described herein. In some circumstances, the compounds described herein have one or more chiral centers, each center being present in an R or S configuration. The compounds described herein include all forms of diastereomers, enantiomers, and epimers, as well as their corresponding mixtures. In a further embodiment of the compounds and methods provided herein, a mixture of enantiomers and / or diastereoisomers derived from a single preparation step, combination, or mutual conversion is described herein. It is useful for applications that are used. In some embodiments, the compounds described herein are prepared as optically pure enantiomers by chiral chromatographic separation of the racemic mixture. In some embodiments, the compounds described herein react a racemic mixture of compounds with an optically active divider to form a pair of diastereoisomeric compounds, separating the diastereomers. , And by recovering optically pure enantiomers, they are prepared as individual stereoisomers. In some embodiments, dissociable complexes are preferred (eg, crystalline diastereomeric salts). In some embodiments, the diastereomers have obvious physical properties (eg, melting point, boiling point, solubility, reactivity, etc.) and are separated by taking advantage of these differences. In some embodiments, the diastereomers are separated by chiral chromatography, or preferably a separation / division technique based on differences in solubility. In some embodiments, the optically pure enantiomer is recovered with the shunting agent by any practical means that does not result in racemization.

Labeled Compounds In some embodiments, the compounds described herein are present in their isotope-labeled form. In some embodiments, the methods disclosed herein include a method of treating a disease by administering such an isotope-labeled compound. In some embodiments, the methods disclosed herein include a method of treating a disease by administering such an isotope-labeled compound as a pharmaceutical composition. Thus, in some embodiments, the compounds disclosed herein include isotope-labeled compounds in which one or more atoms differ from the atomic mass or mass number normally found in nature. It is identical to the compounds listed herein, except that it is replaced by an atom having an atomic mass or mass number. Examples of isotopes incorporated into the compounds described herein are ² H, ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁷ O, ¹⁸ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ respectively. Isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chloride, such as F, and ³⁶ Cl. Compounds described herein, and pharmaceutically acceptable salts, esters, solvates, hydrates thereof, containing the isotopes described above and / or other isotopes of other atoms. Alternatively, the derivative is within the scope of the present invention. Specific isotope-labeled compounds, such as compounds incorporating radioisotopes such as ^3H and ^14C , are useful in drug and / or substrate tissue distribution assays. Tritium-labeled (ie, ^3H ) and carbon-14 (ie, ^14C ) isotopes are particularly preferred for ease of preparation and detectability. In addition, by substituting with deuterium (ie, ^2H ) and other heavy isotopes, certain therapeutic benefits resulting from improved metabolic stability, such as an increase in in vivo half-life or a decrease in required dose. can get. In some embodiments, the isotope-labeled compound, a pharmaceutically acceptable salt, ester, solvate, hydrate, or derivative thereof is prepared by any suitable method.

In some embodiments, the compounds described herein are labeled by other means, including, but not limited to, chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.

Pharmaceutically Acceptable Salts In some embodiments, the compounds described herein are present as pharmaceutically acceptable salts thereof. In some embodiments, the methods disclosed herein include a method of treating a disease by administering such a pharmaceutically acceptable salt. In some embodiments, the methods disclosed herein include a method of treating a disease by administering such a pharmaceutically acceptable salt as a pharmaceutical composition.

In some embodiments, the compounds described herein have an acidic or basic group, and thus by reacting with many inorganic or organic bases, as well as any of the inorganic and organic acids. , Form pharmaceutically acceptable salts. In some embodiments, these salts are in situ during the final isolation and purification of the compounds disclosed herein, or the purified compounds in free form are separated by the appropriate acid or base. It is prepared by reacting with and isolating the salt thus formed.

Solvates In some embodiments, the compounds described herein are present as solvates. In some embodiments, there is a method of treating the disease by administering such a solvate. Further described herein are methods of treating a disease by administering such a solvate as a pharmaceutical composition.

The solvate comprises a stoichiometric or non-stoichiometric amount of solvent and, in some embodiments, during the process of crystallization with a pharmaceutically acceptable solvent such as water, ethanol. It is formed. Hydrate is formed when the solvent is water, and alcohol is formed when the solvent is alcohol. Solvates of the compounds described herein are suitably prepared or formed during the processes described herein. As just one example, the hydrates of the compounds described herein are preferably, but not limited to, by recrystallization from an aqueous / organic solvent mixture using an organic solvent containing dioxane, tetrahydrofuran, or MeOH. Prepared. Moreover, the compounds provided herein are present in solvated and non-solvated forms. Generally, the solvated form is considered equivalent to the non-solvated form for the purposes of the compounds and methods provided herein.

Synthesis of Compounds In some embodiments, the synthesis of the compounds described herein is by means described in the chemical literature, by the methods described herein, or by a combination thereof. Achieved. In addition, the solvents, temperatures, and other reaction conditions presented herein are subject to change.

In other embodiments, the starting materials and reagents used in the synthesis of the compounds described herein are synthesized or, but not limited to, Sigma-Aldrich, Fisher Scientifics, and Acros Organics. Obtained from commercial sources.

In a further embodiment, the compounds described herein, and other related compounds having various substituents, are the techniques and materials described herein, and, for example, the Fieser and Fieser's Reagents for. Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons , 1991), Larock's Compound Organic Transitions (VCH ^Publicsers Inc., 1989), March, Advanced Organic Chemistry 4th Ed. , (Wiley 1992); Carey and ^Sundberg , Advanced Organic Chemistry 4th Ed. , Vols. A and B (Plenum 2000, 2001), and Green and Wuts, Protective Groups in Organic Synthesis 3rd ^Ed . , (Wiley 1999) (all of these documents are incorporated by reference for such disclosure), synthesized using techniques and materials recognized in the art. The general method for the preparation of the compounds disclosed herein may be derived from a reaction, in order to introduce the various parts found in the methods provided herein. , Can be modified with appropriate reagents and conditions. The following synthesis method may be used as a guide.

Use of Protecting Groups In the reactions described, reactive functional groups such as hydroxy, amino, imino, thio, or carboxy groups are not desired for the reaction if desired in the final product. These groups may need to be protected to avoid involvement. Protecting groups are used to block some or all of the reaction moieties and to prevent such groups from engaging in chemical reactions until the protecting groups are removed. It is preferred that each protecting group be removable by different means. Protecting groups cleaved under completely different reaction conditions meet the requirements for differential remote.

Protecting groups can be removed by acids, bases, reducing conditions (eg, hydrocracking, etc.), and / or oxidizing conditions. Groups such as trityl, dimethoxytrityl, acetal, and t-butyldimethylsilyl are acid-labile and protected by Cbz groups (removable by hydrocracking) and Fmoc groups (base-labile). It may be used to protect the reactive moieties of carboxy and hydroxy in the presence of amino groups. Reactive moieties of carboxylic acids and hydroxys are acid-labile groups such as t-butyl carbamate, or the presence of hydrolyzable, hydrolyzable, carbamate-blocked amines that are stable to both acids and bases. Underneath, it can be blocked by base-labile groups such as, but not limited to, methyl, ethyl, and acetyl.

Reactive moieties of carboxylic acids and hydroxys may also be blocked by hydrolysis-removable protecting groups such as benzyl groups, but amine groups capable of hydrogen bonding with acids are unstable to bases such as Fmoc. It may be blocked by the base. Reactive moieties of carboxylic acids can be protected by conversion to simple ester compounds as exemplified herein, including conversion to alkyl esters, or are oxidatively removed, such as 2,4-dimethoxybenzyl. Coexisting amino groups may be blocked by fluoride-labile silylcarbamates, although they may be blocked by possible protecting groups.

Allyl blocking groups are useful in the presence of acid protecting groups and base protecting groups. This is because the former is stable and can be later removed by a metal catalyst or a π acid catalyst. For example, an allyl-blocked carboxylic acid can be deprotected by a Pd ⁰ catalytic reaction in the presence of an acid-labile T-butyl carbamate or a base-labile acetate amine protecting group. However, another form of protecting group is a resin to which a compound or intermediate can be attached. As long as the residue is attached to the resin, its functional groups are blocked and cannot react. Once released from the resin, the functional groups can react.

Typically, blocking / protecting groups are

から選択され得る。

Can be selected from.

A detailed description of other protecting groups and techniques applicable to the formation and removal of protecting groups can be found in Greene and Wuts, Protective Groups in Organic Synthesis, 3rd Ed. , John Wiley & Sons, New York, NY, 1999, and Kocienski, Protecting Groups, Threeme Verlag, New York, NY, 1994, which is incorporated herein by reference for disclosure.

Therapeutic and Prophylactic Methods In some embodiments, there is a method of treating an inflammatory bowel disease in a patient, wherein the method is a therapeutically effective amount of formula (I), (I'), (I''). , (Ia), (Ib), (Ic), or (Id) compound, or a pharmaceutically acceptable salt or admixture thereof, comprising the step of administering to the patient. In some embodiments, there is a method of treating an inflammatory bowel disease in a patient, wherein the method is a therapeutically effective amount of formula (I), (I'), (I''), (Ia),. It comprises administering to said patient a compound of (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or admixture thereof, wherein the inflammatory bowel disease is Crohn's disease. , Inflammatory bowel inflammation, and perianal Crohn's disease. In some embodiments, there is a method of treating an inflammatory bowel disease in a patient, wherein the method is a therapeutically effective amount of formula (I), (I'), (I''), (Ia),. It comprises administering to the patient a compound of (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or admixture thereof, wherein the inflammatory bowel disease is Crohn's disease. be. In some embodiments, there is a method of treating an inflammatory bowel disease in a patient, wherein the method is a therapeutically effective amount of formula (I), (I'), (I''), (Ia),. It comprises administering to the patient a compound of (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or admixture thereof, wherein the inflammatory bowel disease is ulcerative colitis. It is a flame. In some cases, ulcerative colitis is a severe form of ulcerative colitis. In some cases, the severe form of ulcerative colitis is medically refractory ulcerative colitis. In some embodiments, there is a method of treating an inflammatory bowel disease in a patient, wherein the method is a therapeutically effective amount of formula (I), (I'), (I''), (Ia),. It comprises administering to the patient a compound of (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or admixture thereof, wherein the inflammatory bowel disease is a perianal clone. I'm sick.

Pharmaceutical Compositions and Methods of Administration In certain embodiments, the compounds described herein are administered as pure chemicals. In other embodiments, the compounds described herein are described, for example, in Remington: The Science and Practice of Pharmaceutics (Gennaro, 21st Ed. Mack Pub. Co., Easton, PA (2005)). Pharmaceutically suitable or acceptable carriers (in the present specification, pharmaceutically suitable (or acceptable) excipients, selected on the basis of the selected route of administration and standard pharmacological practices. Combined with a physiologically suitable (or acceptable) excipient, or also referred to as a physiologically suitable (or acceptable) carrier.

Accordingly, pharmaceutical compositions are provided herein comprising at least one compound described herein, or a pharmaceutically acceptable salt thereof, along with one or more pharmaceutically acceptable carriers. .. The carrier (or excipient) is acceptable or suitable if it is compatible with the other components of the composition and is not harmful to the recipient (ie, subject) of the composition. ..

In some embodiments, a pharmaceutically acceptable carrier and a compound of formula (I), (I'), (I''), (Ia), (Ib), (Ic), or (Id). , Or a pharmaceutical composition comprising a pharmaceutically acceptable salt or solvate thereof. In some embodiments, there are pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, there are pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, there are pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a compound of formula (I ″), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, there are pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, there are pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, there are pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a compound of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, there are pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a compound of formula (Id), or a pharmaceutically acceptable salt or solvate thereof.

Another embodiment is a pharmaceutically acceptable carrier and a compound of formula (I), (I'), (I''), (Ia), (Ib), (Ic), or (Id). Alternatively, there is provided a pharmaceutical composition comprising substantially from a pharmaceutically acceptable salt or solvate thereof. In some embodiments, there are pharmaceutically acceptable carriers and pharmaceutical compositions substantially consisting of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, there are pharmaceutical compositions substantially consisting of a pharmaceutically acceptable carrier and a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, there are pharmaceutical compositions substantially consisting of a pharmaceutically acceptable carrier and a compound of formula (I ″), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, there are pharmaceutical compositions substantially consisting of a pharmaceutically acceptable carrier and a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, there are pharmaceutical compositions substantially consisting of a pharmaceutically acceptable carrier and a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, there are pharmaceutical compositions substantially consisting of a pharmaceutically acceptable carrier and a compound of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, there are pharmaceutical compositions substantially consisting of a pharmaceutically acceptable carrier and a compound of formula (Id), or a pharmaceutically acceptable salt or solvate thereof.

In certain embodiments, the compounds described herein contain less than about 5% or about 1% of other small organic molecules such as contaminating intermediates or by-products produced in one or more steps of the synthetic method. It is substantially pure in that it contains less than, or less than about 0.1%.

These formulations include formulations suitable for oral, topical, buccal, parenteral (eg, subcutaneous, intramuscular, intradermal, or intravenous) or aerosol administration.

Exemplary pharmaceutical compositions are used in the form of pharmaceutical formulations, eg, solid, semi-solid, or liquid, which are organic or inorganic carriers suitable for external, intestinal, or parenteral applications. Alternatively, it contains one or more of the disclosed compounds as an active ingredient in a mixture with an excipient. In some embodiments, the active ingredient is mixed with, for example, a normally non-toxic and pharmaceutically acceptable carrier, tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, and uses. It is made into another form suitable for. The active subject compound is included in the pharmaceutical composition in an amount sufficient to exert the desired effect on the process or condition of the disease.

In some embodiments for preparing a solid composition such as a tablet, to form a solid preform composition comprising a homogeneous mixture of the disclosed compound or a non-toxic and pharmaceutically acceptable salt thereof. The main active ingredient is a pharmaceutical carrier, such as conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate, or rubber, and other pharmaceutical diluents. , For example, mix with water. When referring to such a preform composition as homogeneous, the active ingredient is spread throughout the composition so that the composition is easily subdivided into equally effective unit dosage forms such as tablets, pills, and capsules. It means that it is uniformly distributed.

In solid dosage forms for oral administration (capsules, tablets, rounds, dragees, powders, granules, etc.), the subject composition is one or more pharmaceutically such as sodium citrate or dicalcium phosphate. It is mixed with an acceptable carrier and / or any of the following: (1) starch, cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, lactose, sucrose, glucose, mannitol, and / or silicic acid and the like. (2) Binding agents such as, for example, carboxymethyl cellulose, hypromerose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and / or acacia; (3) Moisturizing agents such as glycerol; (4) Crospovidone. , Disintegrants such as croscarmellose sodium, sodium starch glycolate, agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) dissolution retarders such as paraffin; (6) 4. Absorption-promoting agents such as quasi-ammonium compounds; (7) wetting agents such as, for example, sodium docusate, cetyl alcohol, and glycerol monostearate; (8) absorbents such as kaolin and bentonite clay; (9). Lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof; and (10) colorants. In the case of capsules, tablets, and pills, in some embodiments, the composition comprises a buffer. In some embodiments, similar types of solid compositions are fillers in soft or tightly packed gelatin capsules that use such excipients as lactose or lactose, as well as high molecular weight polyethylene glycols and the like. Also used as.

In some embodiments, tablets are optionally made by compression or molding with one or more accessory components. In some embodiments, the compressed tablet is a binder (eg gelatin or hydroxypropylmethylcellulose), a lubricant, an inert diluent, a preservative, a disintegrant (eg, sodium starch glycolate or crosslinked sodium carboxylmethylcellulose). ), Surface activator, or dispersant. In some embodiments, molded tablets are made by molding a mixture of subject compositions moistened with an inert liquid diluent with a suitable machine. In some embodiments, tablets and other solid dosage forms such as dragees, capsules, pills, and granules are obtained using coatings and shells such as enteric coatings and other coatings, or Prepared.

A pharmaceutical composition suitable for parenteral administration is one or more pharmaceutically acceptable sterile isotonic water-soluble or water-insoluble solutions, dispersions, suspensions or emulsions, or sterile immediately before use. It contains the composition of interest in combination with a sterile powder reconstituted into an injectable solution or dispersion, which, in some embodiments, is an antioxidant, a buffer, a bacteriostatic agent, the blood of the recipient of interest. Contains solutes, or suspending agents or thickeners that make the formulation isotonic.

Examples of suitable water-soluble and water-insoluble carriers used in pharmaceutical compositions are water, ethanol, polyols (glycerin, propylene glycol, polyethylene glycol, etc.) and suitable mixtures thereof, vegetable oils such as olive oil. , And injectable organic acid esters such as ethyl oleate and cyclodextrin. Appropriate fluidity is maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersion, and by the use of surfactants.

Compositions for inhalation or blowing include solutions and suspensions, or mixtures thereof, and powders in pharmaceutically acceptable aqueous or organic solvents. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the composition of interest, in some embodiments, the liquid dosage form is an inert diluent such as water or other solvent, solubilizers and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, acetic acid. Ethyl, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofuryl alcohol, polyethylene. Includes glycols, fatty acid esters of sorbitan, cyclodextrin, and mixtures thereof.

In some embodiments, the suspension, in addition to the composition of interest, is, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol, and sorbitan ester, microcrystalline cellulose, aluminum metahydroxydo, bentonite. , Agar, and tragant, as well as suspending agents as a mixture thereof.

In some embodiments, the powder and spray are excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate, and polyamide powder, or mixtures of these substances, in addition to the composition of interest. including. In some embodiments, the spraying agent further comprises chlorofluorohydrocarbons, and conventional propellants such as volatile, unsubstituted hydrocarbons such as butane and propane.

The compositions and compounds disclosed herein are administered alternative by aerosol. This is accomplished by preparing an aqueous aerosol containing the compound, a liposome preparation, or solid microparticles. In some embodiments, non-aqueous (eg, fluorocarbon spray) suspensions are used. In some embodiments, a sonic nebulizer is used to minimize exposure of the agent to shear that results in the decomposition of the compounds contained in the composition of interest. Aqueous aerosols are usually made by formulating an aqueous solution or suspension of the composition of interest with conventional pharmaceutically acceptable carriers and stabilizers. Carriers and stabilizers will vary depending on the requirements of the particular composition of interest, but typically nonionic surfactants (tween, pluronic®, or polyethylene glycol), serum albumins, and the like. Examples include harmless proteins, amino acids such as sorbitan esters, oleic acid, lecithin, glycine, buffers, salts, sugars, or sugar alcohols. Aerosols are generally prepared from isotonic solutions.

In some embodiments, the compositions and compounds described herein are administered to a subject in a biologically compatible form suitable for topical administration. Topical administration may be presented in the form of aerosols, semi-solid pharmaceutical compositions, powders, or solutions. The term "semi-solid composition" means an ointment, cream, ointment, jelly, or other pharmaceutical composition with substantially similar viscosity suitable for application to the skin. Examples of semi-solid compositions are the Chapter 17 of The Theory and Practice of Individual Pharmacy, Lachman, Lieberman and Lieberman, published by Mac Publishing Company. It is described in Pharmaceutical Sciences, 15th Edition (1975).

Transdermal or skin patches are another method for transdermal delivery of the therapeutic or pharmaceutical compositions described herein. The patch can provide an absorption enhancer such as DMSO to increase the absorption of the compound. Patches may also include those that control the rate of drug delivery to the skin.

Ointments, pastes, creams, and gels can also contain excipients such as starch, tragant, cellulose derivatives, polyethylene glycol, silicone, bentonite, silicic acid, and talc, or mixtures thereof. Powders and sprays can also contain excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate, and polyamide powder, or mixtures of these substances. Solutions of nanocrystalline antibacterial metals can be converted to aerosols or sprays by any of the known means commonly used to make aerosol pharmaceuticals. In general, such methods provide a means of pressurizing or pressurizing a container of solution, usually with an inert carrier gas, comprising passing the pressurized gas through a small opening. The spray may further include chlorofluorohydrocarbons and conventional propellants such as volatile, unsubstituted hydrocarbons such as butane and propane.

The dose of the composition comprising at least one inhibitory compound as described herein is the patient's (eg, human) condition, ie, stage of disease, general health, age, and other factors. Depends on.

The pharmaceutical composition is administered in an appropriate manner for the disease to be treated (or prevented). The appropriate dose and appropriate time and frequency of administration will be determined by factors such as the patient's condition, the type and severity of the patient's disease, the particular form of the active ingredient, and the method of administration. In general, appropriate dose and treatment regimens have therapeutic and / or prophylactic benefits (eg, improved clinical outcomes, such as frequent complete or partial remissions, or long disease-free survival and / or overall survival. , Or in an amount sufficient to provide relief of the severity of the symptoms, etc.). Optimal doses are generally determined using experimental models and / or clinical trials. In some embodiments, the optimal dose depends on the patient's body shape, weight, or blood volume.

Oral doses typically range from about 1.0 mg to about 1000 mg 1 to 4 times or more per day.

Dosage administration can be repeated depending on the pharmacokinetic parameters of the pharmaceutical product to be administered and the route of administration used.

It is of particular advantage to formulate the composition in dosage unit dosage form for ease of administration and for uniform dosage. Dosage form as used herein refers to physically individual units suitable as unitary doses for a mammalian subject to be treated, each unit required. Contains a predetermined amount of active compound calculated to provide the desired therapeutic effect associated with the pharmaceutical carrier. Dosage form specifications include (a) the unique properties of the compounds of formula (I), (I'), (I''), (Ia), (Ib), (Ic), or (Id). It is determined and directly dependent on the particular therapeutic effect to be achieved, and (b) the inherent limitations in the technique of formulating such active compounds for the treatment of individual hypersensitivity. Specific doses can be readily calculated by one of ordinary skill in the art, for example, according to the patient's approximate body weight or body surface area, or the volume of body space occupied. The dose is further calculated depending on the particular route of administration selected. The exact dose will be determined with a standard dose-response test. The amount of composition actually administered includes the disease to be treated, the choice of composition to be administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the route of administration selected. It will be understood that the judgment will be made by the practitioner, taking into account the relevant environment.

The toxicity and therapeutic effects of compounds of formula (I), (I'), (I''), (Ia), (Ib), (Ic), or (Id) are, for example, LD ₅₀ (50% of the population). To determine the lethal dose) and ED ₅₀ (therapeutically effective dose for 50% of the population), it can be determined by cell culture or standard pharmaceutical procedures in laboratory animals. The dose ratio between toxicity and therapeutic effect is the therapeutic index, which can be expressed as the ratio LD ₅₀ / ED ₅₀ .

The following examples are provided for illustrative purposes and are not intended to limit the scope of the claims provided herein.

As used above and throughout the description of the invention, the following abbreviations shall be understood to have the following meanings, unless otherwise specified:
ACN or MeCN Acetonitrile AcOH AlMe ₃ Tritrimethyl Aluminum Bn Benzyl BOC or Boc t-Butyl Carbamate CDI 1,1'-carbonyldiimidazole Cy ₃ P BF ₄ Tricyclohexylphosphonium Tetrafluoroborate DCE Dichloroethane DCM Dichloromethane DDQ 2,3-dichloro- 5,6-dicyano-p-benzoquinone DIPEA or DIEA diisopropylethylamine DMAP 4- (N, N-dimethylamino) pyridine DMF dimethylformamide DMA N, N-dimethylacetoamide DMSO dimethylsulfoxide equiv Equivalent Et ethyl EtOH ethanol EA or EtOAc Ethyl acetate HPLC High-speed liquid chromatography LAH Aluminum hydride Lithium Me Methyl MeOH Methyl methanol MS Mass analysis NMM N-methylmorpholin NMR Nuclear magnetic resonance Pd (dpppf) Cl ₂ [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II) )
Pd (DTBPF) Cl ₂ [1,1'-bis (di-tert-butylphosphino) ferrocene] dichloropalladium (II)
Pd (OAc) ₂ Palladium (II) Acetate PMB Para-methoxybenzyl TEA Triethylamine TFA Trifluoroacetic Acid THF Tetrahydrofuran

Examples 1: 5- (3-ethoxy- [1,1'-biphenyl] -4-yl) -3,6-dihydro-7H- [1,2,3] triazolo [4,5-d] pyrimidine- Synthesis of 7-on (Compound 101)

Step 1: 4-bromo-2-hydroxybenzonitrile (3.00 g, 15.2 mmol, 1.00 eq) and K2 CO ₃ (4.19 g, 30.3 mmol, _2. ) in DMF (30.0 mL). Ethyl iodide (3.07 g, 19.7 mmol, 1.30 eq) was added to the stirred solution (00 eq) at room temperature. The resulting mixture was stirred overnight. The resulting mixture was diluted with water (100 mL). The precipitated solid was collected by filtration and washed with water (2x20 mL). The resulting solid was dried under an infrared lamp. This gave 4-bromo-2-ethoxybenzonitrile (3 g, 88%) as an off-white solid.

Step 2: Add AlMe ₃ (22.1 mL, 44.2 mmol, 4.00 eq) to a stirred mixture of NH ₄ Cl (2.37 g, 44.2 mmol, 4.00 eq) in toluene (20.0 mL). , N ₂ Dropped at room temperature in an atmosphere. The resulting mixture was stirred at room temperature for 30 minutes. To the above mixture was added 4-bromo-2-ethoxybenzonitrile (2.50 g, 11.1 mmol, 1.00 eq). The resulting mixture was stirred at 110 ° C. for an additional 16 hours. The mixture was cooled to 0 ° C. The reaction was quenched by the addition of methanol (50 mL). The solids were filtered and the filter cake was washed with methanol (3x30 mL) and DCM (3x30 mL). The filtrate was concentrated under reduced pressure until a small amount of solvent remained. The residue was diluted with EA (30 mL) and the precipitated solid was collected by filtration and washed with EA (2x20 mL). The resulting solid was dried with an infrared lamp. As a result, 4-bromo-2-ethoxybenzenecarboxymidamide hydrochloride (3 g, 97%) was obtained as a white solid. LCMS (ESI) = 243.1,245.1 [M + H] ⁺ .

Step 3: To a stirred solution of MeOH (30 mL), Na (0.99 g, 42.9 mmol, 4.00 eq) was added in several batches at room temperature under an _N2 atmosphere. The resulting mixture was stirred until the solids were completely dissolved at room temperature. To the above mixture, 4-bromo-2-ethoxybenzenecarboxymidamide hydrochloride (3.00 g, 10.7 mmol, 1.00 eq) and (E)-(ethyl cyano (hydroxyimino) formate) (3.05 g). , 21.5 mmol, 2.00 eq) was added. The resulting mixture was refluxed overnight. The mixture was cooled to room temperature. The reaction was quenched by the addition of water (100 mL). The mixture was acidified with AcOH to pH 5.0. The precipitated solid was collected by filtration and washed with water (3x20 mL). The resulting solid was dried using infrared light. As a result, 6-amino-2- (4-bromo-2-ethoxyphenyl) -5-nitroso-3H-pyrimidine-4-one (3 g, 82%) was obtained as a green solid. LCMS (ESI) = 338.8, 340.8 [M + H] ⁺ .

Step 4: 6-amino-2- (4-bromo-2-ethoxyphenyl) -5-nitroso-3H-pyrimidine-4-one (2.00 g) in water (20.0 mL) and TEA (4.00 mL) Na 2S ₂ O _{4 (} 3.08 g, 17.7 mmol, 3.00 eq) was added to the stirred solution (5.90 mmol, 1.00 eq) at room temperature. The resulting mixture was stirred at room temperature for 30 minutes. The resulting mixture was diluted with water (20 mL). The mixture was acidified with AcOH to pH 5.0. The precipitated solid was collected by filtration and washed with water (2x10 mL). The resulting solid was dried using infrared light. This gave 5,6-diamino-2- (4-bromo-2-ethoxyphenyl) -3H-pyrimidine-4-one (1 g, 52%) as a green solid. LCMS (ESI) = 325.1, 327.1 [M + H] ⁺ .

Step 5: Sodium nitrite (0) in a stirred solution of 5,6-diamino-2- (4-bromo-2-ethoxyphenyl) -3H-pyrimidine-4-one in HCl (6M) (10.0 mL). .42 g, 6.15 mmol, 2.00 eq) was added in several portions at 0 ° C. The resulting mixture was stirred at room temperature for 1 hour. The resulting mixture was diluted with water (30 mL). The precipitated solid was collected by filtration and washed with water (2x10 mL). By purifying the crude product by preparative HPLC, 5- (4-bromo-2-ethoxyphenyl) -3,6-dihydro-7H- [1,2,3] triazolo [4,5] as a white solid is obtained. -D] Pyrimidine-7-one (600 mg, 58%) was obtained. LCMS (ESI) = 336.0, 337.9 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ12.26 (s, 1H), 7.63 (d, J = 8.2 Hz, 1H), 7.41 (d, J = 1.7 Hz, 1H), 7.30 (dd, J = 8.3, 1.7Hz, 1H), 4.17 (q, J = 6.9Hz, 2H), 1.32 (t, J = 6.9Hz, 3H).

Step 6: 5- (4-bromo-2-ethoxyphenyl) -3,6-dihydro-7H- [1,2,3] in an 8 mL sealed tube purged and maintained in an inert atmosphere of nitrogen. ] Triazolo [4,5-d] pyrimidin-7-one (30 mg, 1 eq), phenylboronic acid (21.7 mg, 2 eq), dioxane (0.5 mL), H ₂ O (0.1 mL), K ₂ CO ₃ (36.9 mg, 3 eq) and Pd (dpppf) Cl ₂ (6.5 mg, 0.1 eq) were added. The resulting solution was stirred in an oil bath at 100 ° C. for 2 hours. The solid was filtered. The resulting mixture was concentrated under vacuum. By purifying the crude product by preparative HPLC, 5- (3-ethoxy- [1,1'-biphenyl] -4-yl) -3,6-dihydro-7H- [1, 2,3] Triazolo [4,5-d] pyrimidin-7-one (Compound 101) (12 mg, 40%) was obtained. LCMS (ESI) = 334 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ12.24 (s, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.79 (d, J = 7.1 Hz, 2H), 7.52 (t, J = 7.3Hz, 2H), 7.44 (q, J = 7.5Hz, 3H), 4.31 (q, J = 6.9Hz, 2H), 1.40 (t) , J = 6.9Hz, 3H)

Example 2: 5- (2-ethoxy-4- (pyridin-3-yl) phenyl) -3,6-dihydro-7H- [1,2,3] triazolo [4,5-d] pyrimidine-7- On (Compound 102) Synthesis

5- (2-ethoxy-4- (pyridin-3-yl) phenyl) -3,6-dihydro-7H- [1,2,3] triazolo [4,5-d] pyrimidine-7-one (Compound 102) ) Are 5- (4-bromo-2-ethoxyphenyl) -3,6-dihydro-7H- [1,2,3] triazolo [4,5-d] pyrimidine-7-one and pyridine-3-ylboron. Prepared from acid using the procedures of Example 1, Step 6. LCMS (ESI) = 335.1 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ12.34 (s, 1H), 9.23 (d, J = 1.8 Hz, 1H), 8.81 (dd, J = 5.2, 1.3 Hz) , 1H), 8.64 (d, J = 8.0Hz, 1H), 7.88 (dd, J = 8.0, 3.6Hz, 2H), 7.61 (s, 1H), 7.55 (Dd, J = 8.0, 1.5Hz, 1H), 4.32 (q, J = 7.0Hz, 2H), 1.39 (t, J = 6.9Hz, 3H).

Example 3: 5- (2-ethoxy-4- (pyrimidine-2-yl) phenyl) -3,6-dihydro-7H- [1,2,3] triazolo [4,5-d] pyrimidin-7- On (compound 103) synthesis

5- (2-ethoxy-4- (pyrimidine-2-yl) phenyl) -3,6-dihydro-7H- [1,2,3] triazolo [4,5-d] pyrimidin-7-one is 5 -From (4-bromo-2-ethoxyphenyl) -3,6-dihydro-7H- [1,2,3] triazolo [4,5-d] pyrimidin-7-one and 2- (tributylstannyl) pyrimidine , Example 1, prepared using the procedure of step 6. LCMS (ESI) = 336.1 [M + H] ⁺ .

Example 4: 5- (2-ethoxy-4- (pyridin-4-yl) phenyl) -3,6-dihydro-7H- [1,2,3] triazolo [4,5-d] pyrimidine-7- On (Compound 104) Synthesis

5- (2-ethoxy-4- (pyridin-4-yl) phenyl) -3,6-dihydro-7H- [1,2,3] triazolo [4,5-d] pyrimidine-7-one is 5 Performed from-(4-bromo-2-ethoxyphenyl) -3,6-dihydro-7H- [1,2,3] triazolo [4,5-d] pyrimidin-7-one and pyridine-4-ylboronic acid. Example 1, prepared using the procedure of step 6. LCMS (ESI) = 335.1 [M + H] ⁺ .

Example 5: 5- (2-ethoxy-4- (pyridin-2-yl) phenyl) -3,6-dihydro-7H- [1,2,3] triazolo [4,5-d] pyrimidine-7- On (Compound 105) Synthesis

5- (2-ethoxy-4- (pyridin-2-yl) phenyl) -3,6-dihydro-7H- [1,2,3] triazolo [4,5-d] pyrimidine-7-one is 5 -From (4-bromo-2-ethoxyphenyl) -3,6-dihydro-7H- [1,2,3] triazolo [4,5-d] pyrimidin-7-one and 2- (tributylstannyl) pyridine , Example 1, prepared using the procedure of step 6. LCMS (ESI) = 335.1 [M + H] ⁺ .

Example 6: Methyl 3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)-[1 , 1'-Biphenyl] -2-carboxylate (Compound 106)

Step 1: 1- (azidomethyl) -4-methoxybenzene (5.00 g, 30.6 mmol, 1.00 eq) and cyanoacetamide (2.58 g, 30.6 mmol, 1.00) in EtOH (50.0 mL). EtONa (6.26 g, 91.9 mmol, 3.00 equivalent) was added to the stirred solution of (equivalent) at room temperature under N ₂ atmosphere. The resulting mixture was stirred at 78 ° C. for 3 hours in an _N2 atmosphere. The mixture was cooled to room temperature. The precipitated solid was collected by filtration and washed with EtOH (2x10 mL). The resulting solid was dried under an infrared lamp. As a result, 5-amino-1-[(4-methoxyphenyl) methyl] -1,2,3-triazole-4-carboxamide (3 g, 40%) was obtained as a gray solid.

Step 2: 4-bromo- ₂ -hydroxybenzaldehyde (2.00 g, 9.949 mmol, 1.00 eq) and K2 CO ₃ (2.75 g, 19.9 mmol, 2.00) in DMF (20.0 mL). Ethyl iodide (1.86 g, 11.9 mmol, 1.20 equivalents) was added to the stirred solution (equivalent) at room temperature. The resulting mixture was stirred at room temperature overnight. The resulting mixture was diluted with water (100 mL). The precipitated solid was collected by filtration and washed with water (2x20 mL). The resulting solid was dried under an infrared lamp. As a result, 4-bromo-2-ethoxybenzenealdehyde (1.9 g, 83%) was obtained as a white solid.

Step 3: 5-amino-1-[(4-Methoxyphenyl) methyl] -1,2,3-triazole-4-carboxamide in AcOH (20.0 mL) (1.50 g, 6.07 mmol, 1.00) DDQ (2.75 g, 12.1 mmol, 2.00 eq) was added to a stirred solution of 4-bromo-2-ethoxybenzaldehyde (2.08 g, 9.10 mmol, 1.50 eq) at room temperature. .. The resulting mixture was stirred at 80 ° C. for 24 hours. The mixture was cooled to room temperature. The resulting mixture was diluted with water (50 mL). The precipitated solid was collected by filtration and washed with water (2x10 mL). The residue was re-dissolved in aqueous sodium hydrogen carbonate solution (50 mL). The precipitated solid was collected by filtration and washed with aqueous sodium hydrogen carbonate solution (2x10 mL) and water (2x10 mL). The resulting solid was dried under an infrared lamp. As a result, as a gray solid, 5- (4-bromo-2-ethoxyphenyl) -3- (4-methoxybenzyl) -3,6-dihydro-7H- [1,2,3] triazolo [4,5- d] Pyrimidine-7-one (Compound 106-A) (1.5 g, crude) was obtained. The crude product (30 mg) was purified by preparative HPLC to give 5- (4-bromo-2-ethoxyphenyl) -3- (4-methoxybenzyl) -3,6-dihydro-7H- as a white solid. [1,2,3] Triazolo [4,5-d] pyrimidin-7-one (7 mg) was obtained. LCMS (ESI) = 456 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ12.44 (s, 1H), 7.68 (d, J = 8.3 Hz, 1H), 7.43 (d, J = 1.5 Hz, 1H), 7.35 (d, J = 8.4Hz, 3H), 6.92 (d, J = 8.7Hz, 2H), 5.69 (s, 2H), 4.18 (q, J = 6.9Hz) , 2H), 3.73 (s, 3H), 1.32 (t, J = 6.9Hz, 3H).

Step 4: 5- (4-bromo-2-ethoxyphenyl) -3- (4-methoxybenzyl) -3,6-dihydro-7H- [1,] in dioxane / _H2O (2 / 0.20 mL) 2,3] Triazolo [4,5-d] pyrimidin-7-one (100 mg, 0.219 mmol, 1.00 eq), 2- (methoxycarbonyl) phenylboronic acid (78.9 mg, 0.438 mmol, 2. Pd (dpppf) Cl ₂ CH ₂ Cl ₂ (17.9 mg, 0.022 mmol, 0.10) in a stirred solution of K ₂ CO ₃ (90.86 mg, 0.657 mmol, 3.00 eq). Equivalent) was added at room temperature in an _N2 atmosphere. The resulting mixture was stirred at 100 ° C. overnight. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with water (2 mL). The precipitated solid was collected by filtration and washed with water (2x2 mL). The resulting solid was dried under an infrared lamp. As a result, as a gray solid, methyl 3'-ethoxy-4'-(3- (4-methoxybenzyl) -7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5] -D] Pyrimidine-5-yl)-[1,1'-biphenyl] -2-carboxylate (100 mg, 89%) was obtained.

Step 5: Methyl 3'-ethoxy-4'-(3- (4-methoxybenzyl) -7-oxo-6,7-dihydro-3H- [1] in 2,2,2-trifluoroacetaldehyde (1 mL) , 2,3] Triazolo [4,5-d] pyrimidin-5-yl)-[1,1'-biphenyl] -2-carboxylate (100 mg, 0.195 mmol, 1 equivalent) at 80 ° C. The mixture was stirred for 2 hours. The mixture was cooled to room temperature. The resulting mixture was diluted with water (5 mL). The precipitated solid was collected by filtration and washed with water (2x1 mL). The resulting solid was dried by infrared light. As a result, as a gray solid, methyl 3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl) -[1,1'-biphenyl] -2-carboxylate (90 mg, crude) was obtained. The crude product (20 mg) is purified by preparative HPLC to give methyl 3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo as a white solid. [4,5-d] pyrimidin-5-yl)-[1,1'-biphenyl] -2-carboxylate (5 mg, 6%) was obtained. LCMS (ESI) = 392.1 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ12.03 (s, 1H), 8.14 (s, 1H), 7.85 (d, J = 7.9 Hz, 1H), 7.79 (d, J = 7.7Hz, 1H), 7.68 (t, J = 7.6Hz, 1H), 7.55 (t, J = 7.4Hz, 2H), 7.09 (s, 1H), 7. 02 (d, J = 8.0Hz, 1H), 4.20 (q, J = 6.7Hz, 2H), 3.66 (s, 3H), 1.38 (t, J = 6.9Hz, 3H) ).

Example 7: Methyl 3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)-[1 , 1'-Biphenyl] -3-carboxylate (Compound 107)

Methyl 3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)-[1,1'- Biphenyl] -3-carboxylate was prepared using the procedures of Example 6, Steps 4 and 5, except that (3- (methoxycarbonyl) phenyl) boronic acid was used in Step 4. LCMS (ESI) = 392.1 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ12.22 (s, 1H), 8.28 (s, 1H), 8.06 (dd, J = 17.6, 7.8 Hz, 2H), 7. 90 (d, J = 7.9Hz, 1H), 7.69 (t, J = 7.8Hz, 1H), 7.52-7.41 (m, 1.8Hz, 2H), 4.32 (q) , J = 6.9Hz, 2H), 3.92 (s, 3H), 1.40 (t, J = 6.9Hz, 3H).

Example 8: Methyl 3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)-[1 , 1'-Biphenyl] -4-carboxylate (Compound 108)

Methyl 3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)-[1,1'- Biphenyl] -4-carboxylate was prepared using the procedures of Example 6, Steps 4 and 5, except that (4- (methoxycarbonyl) phenyl) boronic acid was used in Step 4. LCMS (ESI) = 392.1 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ12.26 (s, 1H), 8.09 (d, J = 8.5 Hz, 2H), 7.96 (d, J = 8.5 Hz, 2H), 7.89 (d, J = 7.9Hz, 1H), 7.56-7.45 (m, 2H), 4.32 (q, J = 7.1Hz, 2H), 3.90 (s, 3H) ), 1.40 (t, J = 6.9Hz, 3H).

Example 9: 3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)-[1, Synthesis of 1'-biphenyl] -2-carboxylic acid (Compound 109)

Methyl 3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] in MeOH / H _2O (2 / 0.4 mL) ] Pyrimidine-5-yl)-[1,1'-biphenyl] -2-carboxylate (70.0 mg, 0.179 mmol, 1.00 eq) in a stirred solution of NaOH (35.8 mg, 0.894 mmol, 5.00 equivalent) was added dropwise at room temperature. The resulting mixture was stirred with. The resulting mixture was diluted with water (10 mL). The aqueous layer was extracted with EA (2x5 mL). The mixture was acidified to pH 3-4 with concentrated HCl. The resulting mixture was extracted with EA (3x5 mL). The combined organic layer was washed with brine (1x10 mL) and dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure. The crude product is purified by preparative HPLC to give it a white solid of 3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5]. -D] Pyrimidine-5-yl)-[1,1'-biphenyl] -2-carboxylic acid (Compound 109) (20.5 mg, 30%) was obtained. LCMS (ESI) = 378.1 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ12.23 (s, 1H), 7.90-7.73 (m, J = 13.7, 4.6 Hz, 2H), 7.69-7.57 (M, J = 7.5, 1.4Hz, 1H), 7.57-7.42 (m, 2H), 7.15 (d, J = 1.2Hz, 1H), 7.07 (dd, dd, J = 8.0, 1.4Hz, 1H), 4.21 (q, J = 6.9Hz, 2H), 1.37 (t, J = 6.9Hz, 3H).

Example 10: 3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)-[1, Synthesis of 1'-biphenyl] -3-carboxylic acid (Compound 110)

3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)-[1,1'-biphenyl ] -3-Carboxylic acid (Compound 110) was prepared from Compound 107 using the procedure of Example 9. LCMS (ESI) = 378.1 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ12.20 (s, 1H), 8.27 (s, 1H), 8.09-7.97 (m, 2H), 7.90 (d, J = 7.9Hz, 1H), 7.66 (t, J = 7.8Hz, 1H), 7.52-7.40 (m, 2H), 4.33 (q, J = 6.9Hz, 2H), 1.40 (t, J = 6.9Hz, 3H).

Example 11: 3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)-[1, Synthesis of 1'-biphenyl] -4-carboxylic acid (Compound 111 palladium (II) acetate)

3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)-[1,1'-biphenyl ] -4-Carboxylic acid (Compound 111) was prepared from Compound 108 using the procedure of Example 9. LCMS (ESI) = 378.1 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ12.04 (s, 1H), 8.06 (d, J = 8.4 Hz, 2H), 7.99-7.87 (m, 3H), 7. 56-7.43 (m, 2H), 4.32 (q, J = 6.8Hz, 2H), 1.40 (t, J = 6.9Hz, 3H).

Example 12: Methyl 5- (3-ethoxy-4- (7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl) phenyl) Synthesis of nicotinate (Compound 112)

Methyl 5- (3-ethoxy-4- (7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl) phenyl) nicotinate (Compound 112) ) Was prepared using the procedures of Example 6, Steps 4 and 5, except that (5- (methoxycarbonyl) pyridine-3-yl) boronic acid was used in Step 4. LCMS (ESI) = 393.2 [M + H] ⁺ .

Example 13: 5- (3-ethoxy-4- (7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl) phenyl) nicotine Synthesis of acid (compound 113)

5- (3-ethoxy-4- (7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl) phenyl) nicotinic acid (Compound 113) ) Was prepared from compound 112 using the procedure of Example 9.

Example 14: Methyl 2- (3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)) -Synthesis of [1,1'-biphenyl] -4-yl) acetate (Compound 114)

Methyl 2- (3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)-[1, 1'-biphenyl] -4-yl) acetate (Compound 114) is described in Example 6, Step 6, except that (4- (2-methoxy-2-oxoethyl) phenyl) boronic acid was used in Step 4. Prepared using procedures 4 and 5. LCMS (ESI) = 406.2 [M + H] ⁺ .

Example 15: 2- (3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)- Synthesis of [1,1'-biphenyl] -4-yl) acetic acid (Compound 115)

2- (3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)-[1,1 '-Biphenyl] -4-yl) acetic acid (Compound 115) was prepared from Compound 114 using the procedure of Example 9. LCMS (ESI) = 392.1 [M + H] ⁺ .

Example 16: Methyl 5- (3-ethoxy-4- (7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl) phenyl) Synthesis of thiophene-2-carboxylate (Compound 116)

Methyl 5- (3-ethoxy-4- (7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl) phenyl) thiophene-2- As the carboxylate (Compound 116), methyl 5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) thiophene-2-carboxylate was used in step 4. Except, it was prepared using the procedure of Example 6, Steps 4 and 5. LCMS (ESI) = 398.1 [M + H] ⁺ .

Example 17: 5- (3-ethoxy-4- (7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl) phenyl) thiophene Synthesis of -2-carboxylic acid (Compound 117)

5- (3-ethoxy-4- (7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl) phenyl) thiophene-2-carboxylic acid The acid (compound 117) was prepared from compound 116 using the procedure of Example 9. LCMS (ESI) = 384.1 [M + H] ⁺ .

Example 18: Methyl 2- (3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)) -Synthesis of [1,1'-biphenyl] -2-yl) acetate (Compound 118)

Methyl 2- (3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)-[1, 1'-biphenyl] -2-yl) acetate (Compound 118) is described in Example 6, Step 6, except that (2- (2-methoxy-2-oxoethyl) phenyl) boronic acid was used in Step 4. Prepared using procedures 4 and 5. LCMS (ESI) = 406.2 [M + H] ⁺ .

Example 19: 2- (3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)- Synthesis of [1,1'-biphenyl] -2-yl) acetic acid (Compound 119)

2- (3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)-[1,1 '-Biphenyl] -2-yl) acetic acid (Compound 119) was prepared from Compound 118 using the procedure of Example 9. LCMS (ESI) = 392.2 [M + H] ⁺ .

Example 20: Ethyl 2-((3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl) )-[1,1'-Biphenyl] -3-yl) Oxy) Acetate (Compound 120) Synthesis

Ethyl 2-((3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)-[1 , 1'-biphenyl] -3-yl) oxy) acetate (Compound 120) is ethyl 2- (3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)). Phenoxy) Acetate was prepared using the procedures of Example 6, Steps 4 and 5, except that it was used in Step 4. LCMS (ESI) = 436.2 [M + H] ⁺ .

Example 21: 2-((3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)) -Synthesis of [1,1'-biphenyl] -3-yl) oxy) acetic acid (Compound 121)

2-((3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)-[1, 1'-biphenyl] -3-yl) oxy) acetic acid (Compound 121) was prepared from Compound 120 using the procedure of Example 9. LCMS (ESI) = 408.2 [M + H] ⁺ .

Example 22: Methyl 5-amino-3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl )-[1,1'-Biphenyl] -3-carboxylate (Compound 122)

Methyl 5-amino-3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)-[1 , 1'-Biphenyl] -3-carboxylate was given in Examples 6, Steps 4 and 5 except that (3-amino-5- (methoxycarbonyl) phenyl) boronate was used in Step 4. Prepared using the procedure of. LCMS (ESI) = 407.2 [M + H] ⁺ .

Example 23: 5-amino-3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl) -Synthesis of [1,1'-biphenyl] -3-carboxylic acid (Compound 123)

5-Amino-3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)-[1, The 1'-biphenyl] -3-carboxylic acid (Compound 123) was prepared from Compound 122 using the procedure of Example 9. LCMS (ESI) = 393.1 [M + H] ⁺ .

Example 24: Methyl 5- (3-ethoxy-4- (7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl) phenyl) Synthesis of picolinate (compound 124)

Methyl 5- (3-ethoxy-4- (7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl) phenyl) picolinate (Compound 124) ) Was prepared using the procedures of Example 6, Steps 4 and 5, except that (6- (methoxycarbonyl) pyridine-3-yl) boronic acid was used in Step 4. LCMS (ESI) = 393.1 [M + H] ⁺ .

Example 25: 5- (3-ethoxy-4- (7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl) phenyl) picolin Synthesis of acid (compound 125)

5- (3-ethoxy-4- (7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl) phenyl) picolinic acid (Compound 125) ) Was prepared from compound 124 using the procedure of Example 9. LCMS (ESI) = 379.1 [M + H] ⁺ .

Example 26: Ethyl 2- (4- (3-ethoxy-4- (7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl) ) Synthesis of phenyl) -1H-pyrazole-1-yl) acetate (Compound 126)

Ethyl 2- (4- (3-ethoxy-4- (7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl) phenyl)- 1H-pyrazole-1-yl) acetate (Compound 126) is ethyl 2- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole- 1-Il) Acetate was prepared using the procedures of Example 6, Steps 4 and 5, except that it was used in Step 4. LCMS (ESI) = 410.2 [M + H] ⁺ .

Example 27: 2- (4- (3-ethoxy-4- (7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)) Synthesis of phenyl) -1H-pyrazole-1-yl) acetic acid (Compound 127)

2- (4- (3-ethoxy-4- (7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl) phenyl) -1H -Pyrazole-1-yl) acetic acid was prepared from compound 126 using the procedure of Example 9. LCMS (ESI) = 382.2 [M + H] ⁺ .

Example 28: 4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl) -3'-propoxy- [1, Synthesis of 1'-biphenyl] -3-carboxylic acid (Compound 128)

4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl) -3'-propoxy- [1,1'-biphenyl ] -3-Carboxylic acid was prepared using the procedure of Example 6 except that 1-iodopropane was used in step 2. LCMS (ESI) = 392.1 [M + H] ⁺ .

Example 29: 5-([1,1'-biphenyl] -4-yl) -3,6-dihydro-7H- [1,2,3] triazolo [4,5-d] pyrimidine-7-on ( Synthesis of compound 129)

5-([1,1'-biphenyl] -4-yl) -3,6-dihydro-7H- [1,2,3] triazolo [4,5-d] pyrimidine-7-one is 4-bromo It was prepared using the procedure of Example 6 except that benzaldehyde was used in step 3. LCMS (ESI) = 290.1 [M + H] ⁺ .

Example 30: 5- (4-Cyclopropyl-2-ethoxyphenyl) -3,6-dihydro-7H- [1,2,3] triazolo [4,5-d] pyrimidine-7-one (Compound 130) Synthesis of

Step 1: 5- (4-bromo-2-ethoxyphenyl) -3- (4-methoxybenzyl) -3,6-dihydro-7H- [1, 2,, in toluene / water (1 / 0.10 mL) 3] Triazolo [4,5-d] pyrimidin-7-one (Compound 106-A) (50.0 mg, 0.110 mmol, 1.00 eq), K ₃ PO ₄ (69.8 mg, 0.329 mmol, 3) In a stirred solution of .00 eq) and cyclopropylboronic acid (18.8 mg, 0.219 mmol, 2.00 eq), tricyclohexylphosphonium tetrafluoroborate (8.07 mg, 0.022 mmol, 0.20 eq) and. Pd (OAc) ₂ (2.46 mg, 0.011 mmol, 0.10 eq) was added at room temperature under N ₂ atmosphere. The resulting mixture was stirred at 100 ° C. overnight. The mixture was cooled to room temperature. By purifying the residue by silica gel column chromatography, 5- (4-cyclopropyl-2-ethoxyphenyl) -3- (4-methoxybenzyl) -3,6-dihydro-7H- [1 , 2,3] Triazolo [4,5-d] pyrimidin-7-one (36 mg, 79%) was obtained. LCMS (ESI) = 418.2 [M + H] ⁺ .

Step 2: 5- (4-Cyclopropyl-2-ethoxyphenyl) -3- (4-methoxybenzyl) -3,6-dihydro-7H- [1,2,3] triazolo [4,5-d] pyrimidine -7-one (36.00 mg, 0.086 mmol, 1.00 eq) and 2,2,2-trifluoroacetaldehyde (1.00 mL) were added to an 8 mL container at room temperature. The resulting mixture was stirred at 80 ° C. for 1.5 hours. The resulting mixture was concentrated under reduced pressure. By purifying the crude product by preparative HPLC, 5- (4-cyclopropyl-2-ethoxyphenyl) -3,6-dihydro-7H- [1,2,3] triazolo [4, 5-d] Pyrimidine-7-one (Compound 130) (9.5 mg, 32%) was obtained. LCMS (ESI) = 298.1 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ): δ 11.12 (s, 1H), 8.22 (s, 1H), 7.84 (d, J = 8.1 Hz, 1H), 6.88 ( d, J = 1.2Hz, 1H), 6.78 (dd, J = 8.1, 1.4Hz, 1H), 4.20 (q, J = 7.0Hz, 2H), 2.06-1 .92 (m, 1H), 1.39 (t, J = 6.9Hz, 3H), 1.09-0.93 (m, 2H), 0.86-0.71 (m, 2H).

Example 31: 5- (2-ethoxy-4- (1H-pyrazole-3-yl) phenyl) -1,6-dihydro-7H- [1,2,3] triazolo [4,5-d] pyrimidine- Synthesis of 7-on (Compound 131)

5- (2-ethoxy-4- (1H-pyrazole-3-yl) phenyl) -1,6-dihydro-7H- [1,2,3] triazolo [4,5-d] pyrimidin-7-one , 1H-pyrazole-3-yl) boronic acid was prepared using the procedures of Example 6, Steps 4 and 5, except that it was used in Step 4. LCMS (ESI) = 324.1 [M + H] ⁺ .

Example 32: 3-ethoxy-4- (7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl) benzoic acid (Compound 132) Synthesis of

Step 1: 5- (4-bromo-2-ethoxyphenyl) -3,6-dihydro-7H- [1,2,3] triazolo [4,5-d] pyrimidin-7-one in MeOH at room temperature (4,5-d) Compound, 101-A) (50 mg, 0.149 mmol, 1 eq), Pd (dpppf) Cl ₂ (10.9 mg, 0.015 mmol, 0.1 eq), and triethylamine (45.2 mg, 0.446 mmol, 3). Equivalent) was added to a 30 mL pressurized tank reactor. The mixture was stirred at 120 ° C. for 3 hours under a CO atmosphere of 10 atm. The resulting mixture was concentrated under reduced pressure. The crude product (40 mg) was used directly in the next step without further purification. The crude product (20 mg) was purified by preparative HPLC to obtain a sample for analysis to obtain methyl 3-ethoxy-4- (7-oxo-6,7-dihydro-3H- [1, 2,3] Triazolo [4,5-d] pyrimidin-5-yl) benzoate (Compound 132-A) (14.1 mg, 26%) was obtained. LCMS (ESI) = 316.2 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ12.47 (s, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.76-7.55 (m, 2H), 4. 21 (q, J = 6.9Hz, 2H), 3.91 (s, 3H), 1.34 (t, J = 6.9Hz, 3H).

Step 2: Methyl 3-ethoxy-4- (7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-] in MeOH / H _2O (1 mL / 0.2 mL) d] Pyrimidine-5-yl) benzoate (30 mg, 0.09 mmol, 1 eq) and NaOH (11.4 mg, 0.28 mmol, 3 eq) were added to an 8 mL vial and the solution was stirred at room temperature for 2 hours. The resulting mixture was filtered and the filter cake was washed with EtOAc (3x5 mL). The filtrate was concentrated under reduced pressure. The residue is dissolved in DMSO (3 mL) and purified by fractionation to give 3-ethoxy-4- (7-oxo-6,7-dihydro-3H- [1,2,3] triazolo as an off-white solid. 4,5-d] Pyrimidine-5-yl) Benzoic acid (Compound 132) (8.5 mg) was obtained. LCMS (ESI) = 302.1 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ12.00 (s, 1H), 7.83 (d, J = 7.8 Hz, 1H), 7.64 (d, J = 10.4 Hz, 2H), 4.21 (q, J = 6.9Hz, 2H), 1.36 (t, J = 6.9Hz, 3H).

Example 33: 5- (2-ethoxy-4- (pyrrolidin-1-carbonyl) phenyl) -3,6-dihydro-7H- [1,2,3] triazolo [4,5-d] pyrimidine-7- Synthesis of on (compound 133)

3-ethoxy-4- (7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl) benzoic acid (50 mg) in DMF (1 mL) , 0.166 mmol, 1 eq) and DIEA (64.4 mg, 0.498 mmol, 3.0 eq) to a stirred solution of HATU (75.7 mg, 0.199 mmol, 1.2 eq) at room temperature. Pyrrolidine (23.6 mg, 0.332 mmol, 2 eq) was added to the above mixture at room temperature. The resulting mixture was stirred at room temperature overnight. By purifying the crude product by preparative HPLC, 5- (2-ethoxy-4- (pyrrolidin-1-carbonyl) phenyl) -3,6-dihydro-7H- [1,2,3] as a white solid is obtained. ] Triazolo [4,5-d] pyrimidin-7-one (5.1 mg, 8%) was obtained. LCMS (ESI) = 355.4 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ12.32 (s, 1H), 7.75 (d, J = 7.8 Hz, 1H), 7.26 (s, 1H), 7.20 (d, J = 7.9Hz, 1H), 4.24-4.12 (m, 2H), 3.49 (t, J = 6.0Hz, 2H), 3.41 (t, J = 5.8Hz, 2H) ), 1.95-1.79 (m, 4H), 1.34 (t, J = 6.9Hz, 3H).

Example 34: 3-ethoxy-4- (7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl) -N-phenylbenzamide ( Synthesis of compound 134)

3-ethoxy-4- (7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl) -N-phenylbenzamide (Compound 134) , Aniline was prepared using the procedure of Example 33, except that aniline was used in the amide coupling step. LCMS (ESI) = 377.1 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ12.30 (s, 1H), 10.37 (s, 1H), 7.86 (d, J = 7.5 Hz, 1H), 7.79 (d, J = 7.7Hz, 2H), 7.73-7.65 (m, 2H), 7.39 (t, J = 7.9Hz, 2H), 7.14 (t, J = 7.4Hz, 1H) ), 4.27 (q, J = 6.9Hz, 2H), 1.38 (t, J = 6.8Hz, 3H).

Example 35: 3-ethoxy-4- (7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl) benzamide (Compound 135) Synthetic

3-ethoxy-4- (7-oxo-6,7-dihydro-1H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl) benzamide (Compound 135) contains ammonium carbonate. It was prepared using the procedure of Example 33, except that it was used in the amide coupling step. LCMS (ESI) = 301.1 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ12.33 (s, 1H), 8.15 (s, 1H), 7.76 (d, J = 7.8 Hz, 1H), 7.66-7. 50 (m, 3H), 4.21 (q, J = 7.1Hz, 2H), 1.36 (t, J = 6.9Hz, 3H).

Example 36: N-Cyclopentyl-3-ethoxy-4- (7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl) benzamide ( Synthesis of compound 136)

In an 8 mL vial, methyl 3-ethoxy-4- (7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl) benzoate (50. 0 mg, 0.159 mmol, 1.00 eq) and cyclopentaneamine (67.5 mg, 0.793 mmol, 5.00 eq) were added at room temperature. The resulting mixture was stirred at 100 ° C. overnight. The mixture was cooled to room temperature. The resulting mixture was diluted with DMSO (3 mL). By purifying the mixture by preparative HPLC, N-cyclopentyl-3-ethoxy-4- (7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5 -D] Pyrimidine-5-yl) benzamide (9.7 mg, 17%) was obtained. LCMS (ESI) = 369.2 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ): δ 12.26 (s, 1H), 8.43 (d, J = 7.1 Hz, 1H), 7.79 (d, J = 8.4 Hz, 1H) ), 7.64-7.52 (m, 2H), 4.34-4.14 (m, 3H), 2.03-1.84 (m, 2H), 1.82-1.47 (m). , 6H), 1.37 (t, J = 6.9Hz, 3H).

The following compound (Compound 137-192) was prepared using a similar method as described in Example 1-36.

Example 37: (5-Methyl-2-oxo-1,3-dioxol-4-yl) Methyl 3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1, 2,, 3] Synthesis of triazolo [4,5-d] pyrimidin-5-yl)-[1,1'-biphenyl] -4-carboxylate (Compound 193)

3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl) in DMF (1.00 mL) -[1,1'-biphenyl] -4-carboxylic acid (50.0 mg, 0.132 mmol, 1.0 eq), HATU (61.0 mg, 0.160 mmol, 1.2 eq), and DIEA (52. 0 mg, 0.402 mmol, 3.0 eq) was added to an 8 mL vial. 4- (Hydroxymethyl) -5-methyl-1,3-dioxolu-2-one (35.0 mg, 0.269 mmol, 2.0 eq) was added at room temperature and the mixture was stirred for 6 hours. By purifying the crude reaction product (4 mL) by preparative HPLC, as an off-white solid (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl) 3'-ethoxy-4'- (7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)-[1,1'-biphenyl] -4-carboxylate (25) .1 mg, 37%) was obtained. LCMS (ESI) = 490.2 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ11.81 (s, 1H), 8.18-8.04 (m, 2H), 8.02-7.89 (m, 3H), 7.48 ( d, J = 7.2Hz, 2H), 5.27 (s, 2H), 4.32 (q, J = 6.9Hz, 2H), 2.25 (s, 3H), 1.41 (t, J = 6.9Hz, 3H).

Example 38: 3'-(Cyclopentyloxy) -4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)- Synthesis of [1,1'-biphenyl] -4-carboxylic acid (Compound 194)

3'-(Cyclopentyloxy) -4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)-[1,1 '-Biphenyl] -4-carboxylic acid was prepared using the procedures of Examples 6 and 9, except that bromocyclopentane was used in Example 6, Step 2. LCMS (ESI) = 418.1 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ8.08 (dd, J = 12.9, 8.1 Hz, 3H), 7.89 (d, J = 8.1 Hz, 2H), 7.46 (d) , J = 8.1Hz, 2H), 5.28-5.19 (m, 1H), 2.09-1.82 (m, 4H), 1.82-1.53 (m, 4H).

Example 39: 2'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)-[1, Synthesis of 1'-biphenyl] -4-carboxylic acid (Compound 195)

2'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)-[1,1'-biphenyl ] -4-Carboxylic acid was prepared using the procedures of Examples 6 and 9. LCMS (ESI) = 378.1 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ7.98 (d, J = 8.0 Hz, 2H), 7.84 (d, J = 7.8 Hz, 2H), 7.66 (d, J = 8) .0Hz, 2H), 7.46 (d, J = 8.1Hz, 1H), 4.23 (q, J = 6.9Hz, 2H), 1.34 (t, J = 6.9Hz, 3H) ..

Example 40: 2', 6'-dimethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)- Synthesis of [1,1'-biphenyl] -4-carboxylic acid (Compound 196)

2', 6'-dimethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)-[1,1 '-Biphenyl] -4-carboxylic acid was prepared using the procedures of Examples 6 and 9. LCMS (ESI) = 394.1 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ7.96 (d, J = 8.2 Hz, 2H), 7.57 (s, 2H), 7.40 (d, J = 8.3 Hz, 2H), 3.81 (s, 6H).

Example 41: 5- (3'-amino-3-ethoxy- [1,1'-biphenyl] -4-yl) -3,6-dihydro-7H- [1,2,3] triazolo [4,5 -D] Synthesis of pyrimidine-7-one (Compound 197)

5- (3'-amino-3-ethoxy- [1,1'-biphenyl] -4-yl) -3,6-dihydro-7H- [1,2,3] triazolo [4,5-d] pyrimidine -7-on was prepared using the procedure of Example 6. LCMS (ESI) = 349.2 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ): δ 11.97 (s, 1H), 7.88 (d, J = 8.5 Hz, 1H), 7.30 (d, J = 6.6 Hz, 2H) ), 7.14 (t, J = 7.8Hz, 1H), 6.94 (t, J = 1.9Hz, 1H), 6.89 (d, J = 7.6Hz, 1H), 6.71. -6.58 (m, 1H), 4.28 (q, J = 6.9Hz, 2H), 1.41 (t, J = 6.9Hz, 3H).

Example 42: 3'-ethoxy-5-hydroxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl) -Synthesis of [1,1'-biphenyl] -3-carboxylic acid (Compound 198)

Step 1: 5- (4-bromo-2-ethoxyphenyl) -3- (4-methoxybenzyl) -3,6-dihydro-7H- in 1,4-dioxane (10 mL) at room temperature under _N2 . [1,2,3] Triazolo [4,5-d] pyrimidin-7-one (1.00 g, 2.19 mmol, 1.0 equivalent) and 4,4,4', 4', 5,5,5 ', 5'-Octamethyl-2,2'-bi (1,3,2-dioxaborolane (1.11 g, 4.37 mmol, 2.0 eq)) and KOAc (645 mg, 6.57 mmol, 3.0 eq) and Pd (dpppf) Cl ₂ (160 mg, 0.219 mmol, 0.10 eq) was added to a 40 mL vial. The resulting mixture was stirred at 100 ° C. for 2 hours, after which the reaction was watered at room temperature. Quenched by adding (100 mL). Precipitated solids were collected by filtration, washed with water (2x10 mL) and petroleum ether (2x10 mL) and dried to give 5- (2-ethoxy-) as brown solids. 4- (4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) -3- (4-Methoxybenzyl) -3,6-dihydro-7H- [1,2 , 3] Triazolo [4,5-d] pyrimidin-7-one (1.3 g, crude) was obtained. LCMS (ESI) = 502.2 [M + H] ⁺ .

Step 2: 5- (2-ethoxy-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) -3- (4-methoxybenzyl) -3, 6-Dihydro-7H- [1,2,3] triazolo [4,5-d] pyrimidin-7-one (50.0 mg, 0.099 mmol, 1.0 eq), 3-bromo-5-hydroxybenzoic acid (32.0 mg, 0.147 mmol, 1.5 eq), K ₂ CO ₃ (41.0 mg, 0.297 mmol, 3.0 eq), Pd (dpppf) Cl ₂ (10 mg, 0.014 mmol, 0.14) Equivalent), dioxane (1.0 mL), and _H2O (0.10 mL) were added to an 8 mL vial. The resulting mixture was heated under N ₂ at 80 ° C. for 2 hours and then cooled to room temperature. The mixture is acidified to pH 4 with HCl (aq.), And the precipitated solid is collected by filtration to obtain 3'-ethoxy-5-hydroxy-4'-(3- (4-methoxybenzyl)-) as a brown solid. 7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)-[1,1'-biphenyl] -3-carboxylic acid (53 mg) Got LCMS (ESI) = 514.2 [M + H] ⁺ .

Step 3: 3'-ethoxy-5-Hydroxy-4'-(3- (4-Methoxybenzyl) -7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-] d] Pyrimidine-5-yl)-[1,1'-biphenyl] -3-carboxylic acid (53.0 mg, 0.103 mmol, 1.0 eq) and trifluoroacetic acid (2.0 mL) were added to the vial. .. The resulting mixture was stirred at 80 ° C. for 2 hours. The mixture was cooled to room temperature. The resulting mixture was concentrated under vacuum. The crude product is purified by preparative HPLC to give 3'-ethoxy-5-hydroxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] as an off-white solid. Triazolo [4,5-d] pyrimidin-5-yl)-[1,1'-biphenyl] -3-carboxylic acid (6.3 mg, 16%) was obtained. LCMS (ESI) = 394.1 [M + H] ⁺ . LCMS (ESI) = 394.1 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ12.00 (s, 1H), 10.00 (s, 1H), 7.90 (d, J = 8.2 Hz, 1H), 7.71 (s, 1H), 7.44-7.33 (m, 4H), 4.31 (q, J = 6.8Hz, 2H).

Example 43: 3'-(Cyclopentyloxy) -5-Hydroxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5 -Il)-[1,1'-biphenyl] -3-carboxylic acid (Compound 199) synthesis

3'-(Cyclopentyloxy) -5-Hydroxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)- [1,1'-Biphenyl] -3-carboxylic acid was prepared using the procedures of Examples 6 and 42, except that bromocyclopentane was used in Step 6 of Example 6. LCMS (ESI) = 434.2 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ10.01 (s, 1H), 7.96 (d, J = 8.2 Hz, 1H), 7.70 (s, 1H), 7.38 (t, J = 7.5Hz, 4H), 2.04-1.78 (m, 4H), 1.67-1.61 (m, 4H).

Example 44: 3'-(Cyclopentyloxy) -4-hydroxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5 -Il)-[1,1'-biphenyl] -3-carboxylic acid (compound 200) synthesis

3'-(Cyclopentyloxy) -4-hydroxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)- [1,1'-biphenyl] -3-carboxylic acid was prepared using the procedure of Example 42. LCMS (ESI) = 434.1 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ12.02 (s, 1H), 8.12 (d, J = 2.5 Hz, 1H), 8.00-7.86 (m, 2H), 7. 46-7.33 (m, 2H), 7.08 (d, J = 8.5Hz, 1H), 5.22 (s, 1H), 2.16-1.74 (m, 4H), 1. 76-1.47 (m, 4H).

Example 45: 3'-(Cyclopentyloxy) -3-hydroxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5 -Il)-[1,1'-biphenyl] -4-carboxylic acid (Compound 201) synthesis

3'-(Cyclopentyloxy) -3-hydroxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)- [1,1'-Biphenyl] -4-carboxylic acid was prepared using the procedure of Example 42. LCMS (ESI) = 434.1 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ7.9 (d, J = 8.3 Hz, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.43-7.33 (m) , 2H), 7.12-7.01 (m, 2H), 5.18 (s, 1H), 1.97-1.91 (m, 2H), 1.87-1.81 (m, 2H) ), 1.67 to 1.61 (m, 4H).

Example 46: 3'-(Cyclopentyloxy) -2-Hydroxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5 -Il)-[1,1'-biphenyl] -4-carboxylic acid (Compound 202) synthesis

3'-(Cyclopentyloxy) -2-Hydroxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)- [1,1'-Biphenyl] -4-carboxylic acid was prepared using the procedure of Example 42. LCMS (ESI) = 434.2 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ12.10 (s, 1H), 7.91 (dd, J = 8.2,5.7 Hz, 2H), 7.47 (s, 2H), 7. 38-7.26 (m, 2H), 5.23 (tt, J = 5.7, 2.7Hz, 1H), 2.04-1.77 (m, 4H), 1.75-1.55 (M, 4H).

Example 47: 5- (3-ethoxy-3', 5'-difluoro-4'-hydroxy- [1,1'-biphenyl] -4-yl) -3,6-dihydro-7H- [1,2 , 3] Synthesis of triazolo [4,5-d] pyrimidin-7-one (Compound 203)

5- (3-ethoxy-3', 5'-difluoro-4'-hydroxy- [1,1'-biphenyl] -4-yl) -3,6-dihydro-7H- [1,2,3] triazolo [4,5-d] Pyrimidine-7-one was prepared using the procedure of Example 42. LCMS (ESI) = 386.2 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ11.95 (s, 1H), 7.91-7.82 (m, 1H), 7.59 (dd, J = 8.3, 1.7 Hz, 2H) ), 7.42 (d, J = 6.8Hz, 2H), 4.32 (q, J = 6.9Hz, 2H), 1.40 (t, J = 6.9Hz, 3H).

Example 48: 3-Amino-3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl) -Synthesis of [1,1'-biphenyl] -4-carboxylic acid (Compound 204)

3-Amino-3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)-[1, The 1'-biphenyl] -4-carboxylic acid was prepared using the procedure of Example 42, except that Pd (DTBPF) Cl ₂ was used in step 2. LCMS (ESI) = 392.4 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ7.92 (d, J = 8.5 Hz, 1H), 7.81 (d, J = 8.3 Hz, 1H), 7.35 (d, J = 6) .8Hz, 2H), 7.14 (d, J = 1.8Hz, 1H), 6.92 (dd, J = 8.4,1.8Hz, 1H), 4.29 (q, J = 6. 9Hz, 2H), 1.41 (t, J = 6.9Hz, 3H).

Example 49: 3'-ethoxy-3-fluoro-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl) -Synthesis of [1,1'-biphenyl] -4-carboxylic acid (Compound 205)

3'-ethoxy-3-fluoro-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)-[1, The 1'-biphenyl] -4-carboxylic acid was prepared using the procedure of Example 48. LCMS (ESI) = 396.1 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ7.99 (d, J = 8.5 Hz, 1H), 7.88 (t, J = 8.1 Hz, 1H), 7.75-7.63 (m) , 2H), 7.52-7.44 (m, 2H), 4.34 (q, J = 6.9Hz, 2H), 1.42 (t, J = 6.9Hz, 3H).

Example 50: 3'-ethoxy-3-methoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl) -Synthesis of [1,1'-biphenyl] -4-carboxylic acid (Compound 206)

3'-ethoxy-3-methoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)-[1, The 1'-biphenyl] -4-carboxylic acid was prepared using the procedure of Example 48. LCMS (ESI) = 408.2 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ8.00 (d, J = 8.0 Hz, 2H), 7.75 (d, J = 7.8 Hz, 2H), 7.48 (dd, J = 9) .6, 1.5Hz, 4H), 7.42 (s, 3H), 7.38 (d, J = 1.5Hz, 1H), 4.34 (q, J = 6.9Hz, 4H), 3 .96 (s, 6H), 1.43 (t, J = 6.9Hz, 6H).

Example 51: 3'-ethoxy-3-methyl-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl) -Synthesis of [1,1'-biphenyl] -4-carboxylic acid (Compound 207)

3'-ethoxy-3-methyl-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)-[1, The 1'-biphenyl] -4-carboxylic acid was prepared using the procedure of Example 48. LCMS (ESI) = 392.2 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ12.89 (s, 1H), 7.95 (d, J = 8.3 Hz, 1H), 7.87 (d, J = 7.8 Hz, 1H), 7.78-7.67 (m, 2H), 7.47 (d, J = 8.2Hz, 2H), 4.31 (t, J = 7.0Hz, 2H), 2.64 (s, 3H) ), 1.40 (t, J = 7.0Hz, 3H).

Example 52: 3'-ethoxy-3-hydroxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl) -Synthesis of [1,1'-biphenyl] -4-carboxylic acid (Compound 208)

3'-ethoxy-3-hydroxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)-[1, The 1'-biphenyl] -4-carboxylic acid was prepared from methyl 4-bromo-2-hydroxybenzoate using the procedures of Examples 48 and 9. LCMS (ESI) = 394.01 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ7.87 (d, J = 8.4 Hz, 1H), 7.74 (d, J = 7.8 Hz, 1H), 7.37 (d, J = 6) .5Hz, 2H), 6.99 (d, J = 10.9Hz, 2H), 4.31 (q, J = 6.9Hz, 2H), 1.39 (t, J = 6.9Hz, 3H) ..

Example 53: 3'-(Cyclopentyloxy) -2-Hydroxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5 -Il)-[1,1'-biphenyl] -3-carboxylic acid (Compound 209) synthesis

3'-(Cyclopentyloxy) -2-Hydroxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)- [1,1'-Biphenyl] -3-carboxylic acid was prepared from methyl 3-bromo-2-hydroxybenzoate using the procedures of Examples 42 and 9. LCMS (ESI) = 434.1 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ12.06 (s, 1H), 7.90 (t, J = 9.2 Hz, 2H), 7.65 (d, J = 7.6 Hz, 1H), 7.45 (s, 1H), 7.38-7.23 (m, 1H), 7.01 (t, J = 7.8Hz, 1H), 5.06 (s, 1H), 2.09- 1.80 (m, 4H), 1.60-1.80 (m, 4H).

Example 54: 3'-(Cyclopentyloxy) -6-Hydroxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5 -Il)-[1,1'-biphenyl] -3-carboxylic acid (compound 210) synthesis

3'-(Cyclopentyloxy) -6-Hydroxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)- [1,1'-Biphenyl] -3-carboxylic acid was prepared from methyl 3-bromo-4-hydroxybenzoate using the procedures of Examples 42 and 9. LCMS (ESI) = 434.2 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ10.63 (s, 1H), 7.99 (d, J = 8.2 Hz, 1H), 7.93 (d, J = 2.2 Hz, 1H), 7.83 (dd, J = 8.5, 2.2Hz, 1H), 7.39 (d, J = 1.6Hz, 1H), 7.28 (dd, J = 8.1, 1.5Hz, 1H), 7.06 (d, J = 8.4Hz, 1H), 5.06 (d, J = 3.5Hz, 1H), 1.80-2.00 (m, 4H), 1.80- 1.51 (m, 4H).

Example 55: 2-((3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)) -Synthesis of [1,1'-biphenyl] -4-yl) oxy) acetic acid (Compound 211)

Step 1: To a 40 mL vial, 4-bromophenol (1.00 g, 5.78 mmol, 1.0 eq) and DMF (10 mL) were added. Potassium carbonate (420 mg, 17.5 mmol, 3.0 eq) was added to the above mixture in several batches at 0 ° C. The resulting mixture was stirred at 0 ° C. for an additional 30 minutes. To the above mixture was added tert-butyl 2-bromoacetate (1.40 g, 7.18 mmol, 1.24 eq). The resulting mixture was stirred at room temperature until TLC analysis showed consumption of starting material. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with EtOAc (3x100 mL). The combined organic layer was washed with brine (3 x 100 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. This gave tert-butyl 2- (4-bromophenoxy) acetate (1.1 g, 66%) as a colorless oil.

Step 2: tert-butyl 2- (4-bromophenoxy) acetate (300 mg, 1.04 mmol, 1.0 eq), bis (pinacolat) diboron (293 mg, 1.15 mmol, 1.1 eq), Pd (dppf). Cl ₂ (60.0 mg, 0.082 mmol, 0.08 eq), KOAc (308 mg, 3.14 mmol, 3.0 eq), and dioxane (5.0 mL) were added to a 40 mL vial. The resulting mixture was stirred under N ₂ at 80 ° C. for 4 hours. The residue is purified by silica gel column chromatography to give tert-butyl 2- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenoxy) as a colorless oil. Acetate (240 mg, 69%) was obtained. LCMS (ESI) = 333.2 [MH] ⁺ .

Step 3: tert-Butyl 2- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenoxy) acetate (80 mg, 0.239 mmol, 1.0 eq) , 5- (4-bromo-2-ethoxyphenyl) -3,6-dihydro-7H- [1,2,3] triazolo [4,5-d] pyrimidine-7-one (120 mg, 0.36 mmol, 1) .5 eq), K ₂ CO ₃ (99.0 mg, 0.716 mmol, 3.0 eq), Pd (dpppf) Cl ₂ (16.0 mg, 0.022 mmol, 0.09 eq), dioxane (2.0 mL) ), And H ₂ O (0.20 mL) were added to an 8 mL vial. The resulting mixture was stirred under N ₂ at 100 ° C. for 16 hours. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure. The crude product is purified by preparative HPLC to give tert-butyl 2-((3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1, 2]) as an off-white solid. , 3] Triazolo [4,5-d] pyrimidin-5-yl)-[1,1'-biphenyl] -4-yl) oxy) acetate (75 mg, 68%) was obtained.

Step 4: tert-butyl 2-((3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5- Il)-[1,1'-biphenyl] -4-yl) oxy) acetate (75.0 mg, 0.162 mmol, 1.0 eq) and 1 M HCl / EtOAc (10 mL) in a 50 mL round bottom flask. Added. The resulting mixture was stirred at 50 ° C. for 16 hours. The crude product is purified by preparative HPLC to give 2-((3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3]) as an off-white solid. Triazolo [4,5-d] pyrimidin-5-yl)-[1,1'-biphenyl] -4-yl) oxy) acetic acid (19.6 mg, 30%) was obtained. LCMS (ESI) = 408.1 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ12.06 (s, 1H), 7.88 (d, J = 8.3 Hz, 1H), 7.74 (d, J = 8.7 Hz, 2H), 7.38 (m, 2H), 7.05 (d, J = 8.7Hz, 2H), 4.75 (s, 2H), 4.31 (q, J = 6.9Hz, 2H), 1. 40 (t, J = 6.9Hz, 3H).

Example 56: (±) -2-((3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-) 5-Il)-[1,1'-biphenyl] -3-yl) Oxy) Propionic acid (Compound 212) synthesis

3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenol (1.00 g, 4.54 mmol, 1.0 eq) in DMF (10.0 mL) and To a stirred solution of methyl ₂ -bromopropanoate (1.14 g, 6.82 mmol, 1.5 eq) was added K2 CO ₃ (1.26 g, 9.09 mmol, 2.0 eq) at room temperature. The resulting mixture was stirred at 60 ° C. for 16 hours, after which the mixture was diluted with water (30 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layer was washed with brine (20 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. By purifying the residue by silica gel column chromatography, methyl 2- [3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenoxy] propanoate as a white solid (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) propanoate ( 520 mg, 37%) was obtained. 2-((3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)-[1, 1'-biphenyl] -3-yl) oxy) propionic acid was prepared using the procedures of Examples 1 and 9. LCMS (ESI) = 422.1 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ8.00 (d, J = 8.5 Hz, 1H), 7.39-7.25 (m, 3H), 7.25-7.12 (m, 2H) ), 6.82 (d, J = 8.0Hz, 1H), 4.45-4.25 (m, 3H), 1.47-1.36 (m, 6H).

Example 57: 2-((3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)) -Synthesis of [1,1'-biphenyl] -3-yl) oxy) -2-methylpropanoic acid (Compound 213)

2-((3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)-[1, 1'-biphenyl] -3-yl) oxy) -2-methylpropionic acid was prepared using the procedures of Examples 56, 1, and 9. LCMS (ESI) = 436.2 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ): δ 7.96 (d, J = 8.5 Hz, 1H), 7.41-7.28 (m, 4H), 7.20 (s, 1H), 6.89 (d, J = 7.1Hz, 1H), 4.31 (q, J = 6.9Hz, 2H), 1.55 (s, 5H), 1.42 (t, J = 6.9Hz) , 3H).

Example 58: (3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)-[1 , 1'-Biphenyl] -3-yl) Glycine (Compound 214)

Step 1: tert-butyl N- (3-bromophenyl) carbamate (1.00 g, 3.68 mmol, 1.0 eq), tert-butyl 2-bromoacetate (1.07 g, 5.51 mmol, 1.5 eq) ), NaH (220 mg, 5.51 mmol, 1.5 eq, 60%), and DMF (10.0 mL) were added to a 40 mL vial at room temperature. The mixture was stirred for 1 hour and then the reaction was quenched with ice water (50 mL). The resulting mixture was extracted with EtOAc (2 x 20 mL). The combined organic layer was washed with brine (1x20 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give tert-butyl N- (3-bromophenyl) -N- (tert-butoxycarbonyl) glycinate (800 mg, 56%) as a colorless oil. LCMS (ESI) = 372 [M + H] ⁺ .

Step 2: tert-butyl N- (3-bromophenyl) -N- (tert-butoxycarbonyl) glycinate (300 mg, 0.777 mmol, 1.0 eq), bis (pinacolat) diboron (296 mg, 1.16 mmol, 1). .5 eq), Pd (dpppf) Cl ₂ (56.8 mg, 0.078 mmol, 0.10 eq), KOAc (229 mg, 2.33 mmol, 3.0 eq), and dioxane (5 mL) in an 8 mL vial. Was added to. The mixture was stirred at 100 ° C. for 2 hours. The resulting mixture is cooled to room temperature, concentrated under reduced pressure and the residue is purified by silica gel column chromatography to give tert-butyl N- (tert-butoxycarbonyl) -N- (3-( 4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) glycinate (270 mg, 80%) was obtained.

Step 3: 5- (4-bromo-2-ethoxyphenyl) -3,6-dihydro-7H- [1,2,3] triazolo [4,5-d] pyrimidin-7-one (70.0 mg, 0) .208 mmol, 1.0 eq), tert-butyl N- (tert-butoxycarbonyl) -N- (3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)) Phenyl) glycinate (135 mg, 0.312 mmol, 1.5 eq), K ₂ CO ₃ (57.6 mg, 0.416 mmol, 2.0 eq), Pd (dpppf) Cl ₂ (15.2 mg, 0.021 mmol, 0.1 eq), dioxane (1 mL), and _H2O (0.3 mL) were added to an 8 mL vial. The resulting mixture was stirred at 100 ° C. for 16 hours. The mixture was cooled to room temperature and acidified to pH 6-7 with 2M HCl. The mixture is purified by silica gel column chromatography to give tert-butyl N- (tert-butoxycarbonyl) -N- (3'-ethoxy-4'-(7-oxo-6,7-dihydro) as an off-white solid. -3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)-[1,1'-biphenyl] -3-yl) glycinate (50 mg, 43%) was obtained.

Step 4: tert-Butyl N- (tert-butoxycarbonyl) -N- (3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,] 5-d] Pyrimidine-5-yl)-[1,1'-biphenyl] -3-yl) glycinate (50.0 mg, 0.089 mmol, 1.0 eq) and TFA (1.0 mL) 8 mL at room temperature Was added to the vial. The resulting mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure. The resulting mixture is diluted with DMSO (2 mL) and then purified by preparative HPLC to give (3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H)-(7-oxo-6,7-dihydro-3H) as a white solid. -[1,2,3] triazolo [4,5-d] pyrimidin-5-yl)-[1,1'-biphenyl] -3-yl) glycine (9.1 mg, 25%) was obtained. LCMS (ESI) = 407.1 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ7.95 (d, J = 8.4 Hz, 1H), 7.32 (dd, J = 4.4, 2.8 Hz, 2H), 7.21 (t) , J = 7.8Hz, 1H), 6.95 (d, J = 9.1Hz, 2H), 6.62 (d, J = 8.5Hz, 1H), 4.30 (q, J = 6. 8Hz, 2H), 3.86 (s, 2H), 1.42 (t, J = 6.9Hz, 3H).

Example 59: (3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)-[1 , 1'-Biphenyl] -4-yl) Glycine (Compound 215)

(3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)-[1,1'- Biphenyl] -4-yl) glycine was prepared using the procedure of Example 58. LCMS (ESI) = 407.2 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ7.95 (d, J = 8.6 Hz, 1H), 7.56 (d, J = 8.6 Hz, 2H), 7.36-7.27 (m) , 2H), 6.68 (d, J = 8.6Hz, 2H), 4.31 (q, J = 6.9Hz, 2H), 3.82 (s, 2H), 1.43 (t, J) = 6.9Hz, 3H).

Example 60: 2-((3'-(cyclopentyloxy) -4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5) -Il)-[1,1'-biphenyl] -3-yl) Oxy) Acetic acid (Compound 216) synthesis

Step 1: 5- (4-bromo-2- (cyclopentyloxy) phenyl) -3- (4-methoxybenzyl) -3,6-dihydro-7H- [1,2,3] triazolo [4,5-d ] Pyrimidin-7-one (200 mg, 0.403 mmol, 1.0 eq) and tert-butyl 2- (3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) ) Phenoxy) acetate (202 mg, 0.604 mmol, 1.5 eq), K ₂ CO ₃ (167 mg, 1.21 mmol, 3.0 eq), Pd (dppf) Cl ₂ CH ₂ Cl ₂ (32.9 mg, 0) .040 mmol, 0.10 eq), dioxane (3.0 mL), and _H2O (0.30 mL) were added to an 8 mL vial. The mixture was stirred at 100 ° C. for 2 hours. The mixture is cooled to room temperature and the residue is purified by silica gel column chromatography to give tert-butyl 2-((3'-(cyclopentyloxy) -4'-(3- (4-methoxybenzyl)) as an off-white solid. -7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)-[1,1'-biphenyl] -3-yl) oxy) Acetate (250 mg) was obtained.

Step 2: tert-butyl 2-((3'-(cyclopentyloxy) -4'-(3- (4-methoxybenzyl) -7-oxo-6,7-) in EA (5.0 mL saturated solution)) Dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)-[1,1'-biphenyl] -3-yl) oxy) acetate (250 mg, 0.401 mmol, 1 .0 eq) and HCl (gas) were added to a 40 mL vial. The resulting mixture was stirred at 50 ° C. for 3 hours. By concentrating the resulting mixture under reduced pressure, 2-((3'-(cyclopentyloxy) -4'-(3- (4-methoxybenzyl) -7-oxo-6,7-dihydro-3H) -[1,2,3] triazolo [4,5-d] pyrimidin-5-yl)-[1,1'-biphenyl] -3-yl) oxy) acetic acid (200 mg), and more. It was used in the next step without purification.

Step 3: 2-((3'-(cyclopentyloxy) -4'-(3- (4-methoxybenzyl) -7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4] , 5-d] Pyrimidine-5-yl)-[1,1'-biphenyl] -3-yl) Oxy) Acetic acid (200 mg, 0.352 mmol, 1.0 eq) and TFA (3.0 mL), 8 mL Was added to the vial. The mixture was stirred at 60 ° C. for 2 hours. The mixture is concentrated under reduced pressure and the crude residue is purified by preparative HPLC to give 2-((3'-(cyclopentyloxy) -4'-(7-oxo-6,7-dihydro)-(7-oxo-6,7-dihydro) as a white solid. -3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)-[1,1'-biphenyl] -3-yl) oxy) acetic acid (19.6 mg, 12%) Obtained. LCMS (ESI) = 448.2 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ8.05 (d, J = 8.4 Hz, 1H), 7.46-7.36 (m, 3H), 7.33 (d, J = 7.8 Hz) , 1H), 7.24 (s, 1H), 6.96 (d, J = 8.2Hz, 1H), 5.23 (s, 1H), 4.68 (s, 2H), 2.02- 1.86 (m, 4H), 1.81-1.51 (m, 4H).

Example 61: 2-((2'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)) -Synthesis of [1,1'-biphenyl] -3-yl) oxy) acetic acid (Compound 217)

2-((2'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)-[1, 1'-biphenyl] -3-yl) oxy) acetic acid was prepared using the procedure of Example 60. LCMS (ESI) = 408.1 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ12.68 (s, 1H), 7.88-7.79 (m, 2H), 7.50 (d, J = 8.3 Hz, 1H), 7. 36 (t, J = 7.9Hz, 1H), 7.23-7.09 (m, 2H), 6.92 (dd, J = 8.7, 2.6Hz, 1H), 4.72 (s) , 2H), 4.22 (q, J = 6.9Hz, 2H), 1.35 (t, J = 6.9Hz, 3H).

Example 62: Methyl 3'-ethoxy-5- (2-methoxy-2-oxoethoxy) -4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4, Synthesis of 5-d] pyrimidin-5-yl)-[1,1'-biphenyl] -3-carboxylate (Compound 218)

Methyl 3'-ethoxy-5- (2-Methoxy-2-oxoethoxy) -4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] Pyrimidine-5-yl)-[1,1'-biphenyl] -3-carboxylate was prepared from methyl 3-bromo-5-hydroxybenzoate and methylbromoacetate using the procedure of Example 55. LCMS (ESI) = 480.2 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ7.99 (d, J = 8.5 Hz, 1H), 7.90 (s, 1H), 7.63 (s, 1H), 7.51-7. 41 (m, 3H), 5.03 (s, 2H), 4.35 (t, J = 6.9Hz, 2H), 3.91 (s, 3H), 3.73 (s, 3H), 1 .42 (t, J = 6.9Hz, 3H).

Example 63: 5- (carboxymethoxy) -3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5 -Il)-[1,1'-biphenyl] -3-carboxylic acid (Compound 219) synthesis

5- (Carboxymethoxy) -3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)- [1,1'-Biphenyl] -3-carboxylic acid was synthesized from compound 218 using the procedure of Example 9. LCMS (ESI) = 452.1 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ8.01 (d, J = 8.1 Hz, 1H), 7.78 (s, 1H), 7.32 (m, 4H), 4.47-4. 24 (m, 4H), 1.42 (t, J = 7.0Hz, 3H).

Example 64: 3- (carboxymethoxy) -3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5 -Il)-[1,1'-biphenyl] -4-carboxylic acid (compound 220) synthesis

3- (Carboxymethoxy) -3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)- [1,1'-Biphenyl] -4-carboxylic acid was synthesized from methyl 4-bromo-2-hydroxybenzoate and methyl bromoacetate using the procedures of Examples 55, 42, and 9. LCMS (ESI) = 452.1 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ12.25 (s, 1H), 7.86 (d, J = 8.4 Hz, 1H), 7.67 (d, J = 8.0 Hz, 1H), 7.57 (s, 1H), 7.46 (d, J = 6.7Hz, 3H), 4.79 (s, 2H), 4.32 (q, J = 6.9Hz, 2H), 1. 39 (t, J = 6.9Hz, 3H).

Example 65: tert-butyl (3'-ethoxy-4-((4-methoxybenzyl) oxy) -4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [ 4,5-d] Pyrimidine-5-yl)-[1,1'-biphenyl] -3-yl) Glycinate (Compound 221) Synthesis

Step 1: 4-bromo-2-nitrophenol (1.00 g, 4.59 mmol, 1.0 equivalent), 4-chloroanisole (0.90 g, 6.31 mmol, 1.4 equivalent), K ₂ CO ₃ ( 1.90 g, 13.7 mmol, 3.0 equivalents), and acetone (20 mL) were placed in a 100 mL round bottom flask. The resulting solution was stirred at 60 ° C. overnight. The resulting mixture was concentrated under vacuum and the residue was purified by silica gel chromadography with ethyl acetate / petroleum ether (5/95) to give 4-bromo-1- ((4)) as a yellow oil. -Methoxybenzyl) oxy) -2-nitrobenzene (850 mg, 57%) was obtained. LCMS (ESI) = 338.0 [M + H] ⁺ .

Step 2: 4-bromo-1-((4-methoxybenzyl) oxy) -2-nitrobenzene (850 mg, 2.51 mmol, 1.0 eq) in EtOH (20 mL) and H2O ( ₂ mL), NH ₄ Cl (668 mg, 12.5 mmol, 5.0 eq) and Fe (420 mg, 7.52 mmol, 3.0 eq) were added to a 100 mL round bottom flask. The resulting solution was stirred at 70 ° C. for 20 minutes. The solid was filtered and the resulting mixture was concentrated under vacuum to give 5-bromo-2-((4-methoxybenzyl) oxy) aniline (700 mg, 90%) as a brown solid. LCMS (ESI) = 308.0 [M + H] ⁺ .

tert-butyl (3'-ethoxy-4-((4-methoxybenzyl) oxy) -4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-] d] Pyrimidine-5-yl)-[1,1'-biphenyl] -3-yl) glycinate (Compound 221) was prepared using the procedure of Example 58. LCMS (ESI) = 599.3 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ12.14 (s, 1H), 7.84 (d, J = 8.2 Hz, 1H), 7.49-7.40 (m, 2H), 7. 34 (d, J = 7.5Hz, 2H), 7.09-6.95 (m, 3H), 6.97 (d, J = 2.0Hz, 1H), 6.79 (d, J = 1) 9.9Hz, 1H), 5.26 (t, J = 5.9Hz, 1H), 5.13 (s, 2H), 4.29 (q, J = 6.9Hz, 2H), 3.98 (d) , J = 5.9Hz, 2H), 3.78 (s, 3H), 1.43 (s, 9H), 1.39 (t, J = 6.9Hz, 3H).

Example 66: (3'-ethoxy-4-hydroxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl) )-[1,1'-biphenyl] -3-yl) Synthesis of glycine (Compound 222)

(3'-ethoxy-4-hydroxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)-[1 , 1'-biphenyl] -3-yl) glycine was prepared from compound 221 using the method of Example 55, Step 4. LCMS (ESI) = 423.1 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ8.01 (d, J = 8.2 Hz, 1H), 7.29 (d, J = 7.7 Hz, 2H), 6.84 (s, 1H), 6.81-6.70 (m, 2H), 4.30 (t, J = 6.9Hz, 2H), 3.71 (s, 2H), 1.44 (t, J = 6.9Hz, 3H) ).

Example 67: (3'-ethoxy-5-hydroxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl) )-[1,1'-biphenyl] -3-yl) Synthesis of glycine (Compound 223)

(3'-ethoxy-5-Hydroxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)-[1 , 1'-biphenyl] -3-yl) glycine, 3-bromo-5-nitrophenol and 5- (2-ethoxy-4- (4,4,5), using the procedures of Examples 65 and 60. , 5-Tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) -3- (4-methoxybenzyl) -3,6-dihydro-7H- [1,2,3] Triazolo [4,5 -D] Prepared from pyrimidine-7-one. LCMS (ESI) = 423.2 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ9.20 (s, 1H), 7.93 (d, J = 8.4 Hz, 1H), 7.25 (dt, J = 4.6, 2.3 Hz) , 2H), 6.43-6.32 (m, 2H), 6.04 (d, J = 2.1Hz, 1H), 4.28 (q, J = 6.8Hz, 2H), 3.78 (S, 2H), 1.42 (t, J = 6.9Hz, 3H).

Example 68: 2-((3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)) -Synthesis of [1,1'-biphenyl] -3-yl) amino) -2-methylpropanoic acid (Compound 224)

In a 40 mL vial, 3-bromoaniline (1.00 g, 5.81 mmol, 1.0 eq) in DMF (10 mL), tert-butyl 2-bromo-2-methylpropanoate (1.50 g, 6). A mixture of .72 mmol) and NaHCO ₃ (1.50 g, 17.9 mmol) was heated at 140 ° C. for 16 hours. The mixture is cooled to room temperature and the residue is purified by silica gel column chromatography to give tert-butyl 2-((3-bromophenyl) amino) -2-methylpropanol (120 mg, 7%) as a brown oil. rice field. ^{1 1} H NMR (300 MHz, CDCl ₃ ) δ7.03 (t, J = 8.0 Hz, 1H), 6.95-6.82 (m, 2H), 6.63 (d, J = 8.0 Hz, 1H) ), 1.55 (s, 6H), 1.43 (s, 9H).

2-((3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)-[1, 1'-biphenyl] -3-yl) amino) -2-methylpropanoic acid is 5- (2-ethoxy-4- (4), using a similar method as described in Examples 42 and 60. , 4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) -3- (4-Methoxybenzyl) -3,6-dihydro-7H- [1,2,3] triazolo [4,5-d] Prepared from pyrimidine-7-one. ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ11.94 (s, 1H), 7.87 (d, J = 8.3 Hz, 1H), 7.30-7.13 (m, 3H), 6. 93 (d, J = 7.6Hz, 1H), 6.86 (t, J = 2.0Hz, 1H), 6.59-6.50 (m, 1H), 4.27 (q, J = 6) .8Hz, 2H), 1.48 (s, 6H), 1.41 (t, J = 6.9Hz, 3H).

Example 69: (3'-(cyclopentyloxy) -4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)) -Synthesis of [1,1'-biphenyl] -3-yl) glycine (Compound 225)

(3'-(Cyclopentyloxy) -4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)-[1, 1'-biphenyl] -3-yl) glycine was prepared using the procedure of Example 58. LCMS (ESI) = 447.2 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ12.03 (s, 1H), 7.92 (d, J = 8.4 Hz, 1H), 7.34 (dq, J = 3.5, 1.6 Hz) , 2H), 7.23 (t, J = 7.8Hz, 1H), 7.02-6.92 (m, 2H), 6.67 (dd, J = 7.8, 2.2Hz, 1H) , 5.15 (dt, J = 5.7, 3.0Hz, 1H), 3.92 (s, 2H), 2.06-1.79 (m, 4H), 1.77-1.53 ( m, 4H).

Example 70: 3-((3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)) -Synthesis of [1,1'-biphenyl] -3-yl) amino) propanoic acid (Compound 226)

5- (3'-amino-3-ethoxy- [1,1'-biphenyl] -4-yl) -3- (4-methoxybenzyl) -3,6-dihydro-7H- [1,2,3] Triazolo [4,5-d] pyrimidin-7-one was prepared using the procedure of Example 1.

Step 1: 5- (3'-amino-3-ethoxy- [1,1'-biphenyl] -4-yl) -3- (4-methoxybenzyl) -3,6- in AcOH (1.0 mL) Dihydro-7H- [1,2,3] triazolo [4,5-d] pyrimidin-7-one (80.0 mg, 0.171 mmol, 1.0 eq) and ethyl 3-oxopropanoate (0.50 mL) ), NaBH (OAc) ₃ (362 mg, 1.71 mmol, 10 eq) was added in several portions at room temperature. The resulting mixture was stirred for 10 minutes and then the resulting mixture was diluted with water (10 mL). The mixture was based to pH 8 with NaHCO ₃ and the resulting mixture was extracted with EA (3 x 10 mL). The combined organic layer was washed with brine (20 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give ethyl 3-((3'-ethoxy-4'-(3- (4-methoxybenzyl) -7-oxo-6,7-dihydro-) as a pale yellow solid. 3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)-[1,1'-biphenyl] -3-yl) amino) propanoate (65 mg, 40%) was obtained.

3-((3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)-[1, 1'-biphenyl] -3-yl) amino) propionic acid was prepared using the procedures of Examples 6 and 9. LCMS (ESI) = 421.2 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ7.91 (d, J = 8.3 Hz, 1H), 7.33 (d, J = 7.4 Hz, 2H), 7.21 (t, J = 7) 9.9Hz, 1H), 6.97-6.88 (m, 2H), 6.64 (dd, J = 7.3, 1.9Hz, 1H), 4.29 (q, J = 6.9Hz, 2H), 3.33 (t, J = 6.7Hz, 2H), 2.58-2.50 (m, 2H), 1.40 (t, J = 6.9Hz, 3H).

Example 71: 4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl) -3'-(2- (pyrrolidin) Synthesis of -1-yl) ethoxy- [1,1'-biphenyl] -4-carboxylic acid (Compound 227)

5- (4-bromo-2-methoxyphenyl) -3- (4-methoxybenzyl) -3,6-dihydro-7H- [1,2,3] triazolo [4,5-d] pyrimidin-7-one Was prepared using the procedure of Example 6.

Step 1: 5- (4-bromo-2-methoxyphenyl) -3- (4-methoxybenzyl) -3,6-dihydro-7H- [1,2,3] triazolo in DMF (5.0 mL) [1,2,3] 4,5-d] NaH (90.4 mg, 2.26 mmol, 2.0 eq, 60%) under _N2 in a stirred solution of pyrimidine-7-one (500 mg, 1.13 mmol, 1.0 eq). It was added in several portions at room temperature. The resulting mixture was stirred at room temperature for 30 minutes, after which 4-methoxybenzyl chloride (212 mg, 1.36 mmol, 1.2 eq) was added dropwise. The resulting mixture was stirred for 24 hours and then quenched by the addition of water (20 mL). The mixture was extracted with EA (2 x 20 mL), the combined organic layer was washed with brine (20 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. By purifying the residue by silica gel column chromatography, 5- (4-bromo-2-methoxyphenyl) -3,6-bis (4-methoxybenzyl) -3,6-dihydro-7H- [ 1,2,3] Triazolo [4,5-d] pyrimidin-7-one (370 mg, 58%) was obtained.

Step 2: 5- (4-bromo-2-methoxyphenyl) -3,6-bis (4-methoxybenzyl) -3,6-dihydro-7H- [1,2,3] in DMF (5.0 mL) ] LiCl (188 mg, 4.44 mmol, 10 eq) was added to a stirred solution of triazolo [4,5-d] pyrimidin-7-one (250 mg, 0.445 mmol, 1.0 eq). The resulting mixture was stirred at 150 ° C. for 9 hours and then cooled to room temperature. The reaction was quenched by the addition of water (20 mL) and acidified to pH 3-4 with concentrated HCl. The mixture was extracted with EA (3 x 10 mL), the combined organic layer was washed with brine (20 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. By purifying the residue by silica gel column chromatography, 5- (4-bromo-2-hydroxyphenyl) -3,6-bis (4-methoxybenzyl) -3,6-dihydro-7H- [ 1,2,3] Triazolo [4,5-d] pyrimidin-7-one (230 mg, 55%) was obtained.

Step 3: 5- (4-bromo-2-hydroxyphenyl) -3,6-bis (4-methoxybenzyl) -3,6-dihydro in dioxane (3.0 mL) and _H2O (0.30 mL) -7H- [1,2,3] triazolo [4,5-d] pyrimidin-7-one (200 mg, 0.212 mmol, 1.0 eq) and 4- (ethoxycarbonyl) phenylboronic acid (61.6 mg, In a solution of 0.317 mmol, 1.5 eq), K ₂ CO ₃ (87.7 mg, 0.635 mmol, 3.0 eq) and Pd (dpppf) Cl ₂ CH ₂ Cl ₂ (15.5 mg, 0.021 mmol). , 0.10 equivalent) was added. After stirring under N ₂ at 100 ° C. for 2 hours, the mixture was concentrated under reduced pressure. By purifying the residue by silica gel column chromatography, ethyl 4'-(3,6-bis (4-methoxybenzyl) -7-oxo-6,7-dihydro-3H- [1, 2,, 3] Triazolo [4,5-d] pyrimidin-5-yl) -3'-hydroxy- [1,1'-biphenyl] -4-carboxylate (150 mg, 34%) was obtained.

Step 4: Ethyl 4'-(3,6-bis (4-methoxybenzyl) -7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4] in DMF (2.0 mL) , 5-d] Pyrimidine-5-yl) -3'-hydroxy- [1,1'-biphenyl] -4-carboxylate (150 mg, 0.243 mmol, 1.0 eq) and 1- (2-chloroethyl) K ₂ CO ₃ (30.2 mg, 0.219 mmol, 3.0 eq) was added to a stirred solution of pyrrolidine hydrochloride (12.4 mg, 0.073 mmol, 1.0 eq) at room temperature. The resulting mixture was stirred at 80 ° C. for 2 hours. The resulting mixture was diluted with water (10 mL). The resulting mixture was extracted with EA (3x5 mL). The combined organic layer was washed with brine (10 mL) and dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure. By purifying the residue by silica gel column chromatography, ethyl 4'-(3,6-bis (4-methoxybenzyl) -7-oxo-6,7-dihydro-3H- [1, 2,, 3] Triazolo [4,5-d] pyrimidin-5-yl) -3'-(2- (pyrrolidin-1-yl) ethoxy)-[1,1'-biphenyl] -4-carboxylate (65 mg, 37) %) Was obtained.

4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl) -3'-(2- (pyrrolidin-1-yl) ) Ethoxy)-[1,1'-biphenyl] -4-carboxylic acid was prepared using the procedures of Examples 6 and 9. LCMS (ESI) = 447.2 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ8.06 (d, J = 8.3 Hz, 2H), 8.02-7.91 (m, 3H), 7.64 (d, J = 1.7 Hz) , 1H), 7.53 (dd, J = 8.1, 1.6Hz, 1H), 4.54 (s, 2H), 3.01 (s, 2H), 2.77 (s, 4H), 1.76 (s, 4H).

Example 72: 3'-(2- (dimethylamino) ethoxy) -4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin- 5-Il)-[1,1'-biphenyl] -4-carboxylic acid (Compound 228) synthesis

3'-(2- (dimethylamino) ethoxy) -4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl) -[1,1'-Biphenyl] -4-carboxylic acid was prepared using the procedure of Example 71. LCMS (ESI) = 421.2 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ8.13-8.04 (m, 2H), 8.00-7.91 (m, 2H), 7.81 (d, J = 8.0 Hz, 1H) ), 7.62-7.50 (m, 2H), 4.62 (d, J = 5.1Hz, 2H), 3.53-3.45 (m, 2H), 2.82 (s, 6H) ).

Example 73: 3'-(3- (dimethylamino) propoxy) -4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin- 5-Il)-[1,1'-biphenyl] -4-carboxylic acid (Compound 229) synthesis

3'-(3- (dimethylamino) propoxy) -4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl) -[1,1'-Biphenyl] -4-carboxylic acid was prepared using the procedure of Example 71. LCMS (ESI) = 435.2 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ11.06 (s, 1H), 8.33 (s, 1H), 8.02-7.93 (m, 3H), 7.79 (d, J = 8.1Hz, 2H), 7.42 (d, J = 8.9Hz, 2H), 4.30 (t, J = 6.1Hz, 2H), 2.57 (t, J = 7.0Hz, 2H) ), 2.26 (s, 6H), 1.99 (q, J = 6.6Hz, 2H).

Example 74: (4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl) -3'-(2-( Synthesis of pyrrolidine-1-yl) ethoxy)-[1,1'-biphenyl] -3-yl) glycine (Compound 230)

(4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl) -3'-(2- (pyrrolidin-1-) Il) ethoxy)-[1,1'-biphenyl] -3-yl) glycine is Example 71, except that alkylation with 1- (2-chloroethyl) pyrrolidine hydrochloride was performed in step 2. And the rest of the steps were carried out as in Example 58. LCMS (ESI) = 476.2 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ7.93 (d, J = 8.1 Hz, 1H), 7.46 (d, J = 1.6 Hz, 1H), 7.38 (dd, J = 8) .0, 1.5Hz, 1H), 7.21 (t, J = 7.8Hz, 1H), 7.02-6.91 (m, 2H), 6.64 (d, J = 8.3Hz, 1H), 4.51 (s, 2H), 3.90 (s, 2H), 3.03 (s, 2H), 2.79 (s, 4H), 1.77 (s, 4H).

Example 75: 6- (3- (cyclopentyloxy) -4- (7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)) Synthesis of phenyl) nicotinic acid (Compound 231)

6- (3- (Cyclopentyloxy) -4- (7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl) phenyl) nicotinic acid Was prepared from 6-bromonicotinic acid using the procedure of Example 42. LCMS (ESI) = 419.1 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ13.6 (road s, 1H), 12.2 (road s, 1H), 9.20 (s, 1H), 8.39 (dd, J = 8. 1,2.1Hz, 1H), 8.26 (d, J = 8.4Hz, 1H), 7.80-8.00 (m, 3H), 5.10-5.20 (m, 1H), 1.75-2.05 (m, 4H), 1.55-1.75 (m, 4H).

Example 76: 5- (3-ethoxy-3'-(methylamino)-[1,1'-biphenyl] -4-yl) -3,6-dihydro-7H- [1,2,3] triazolo [ 4,5-d] Synthesis of pyrimidine-7-one (Compound 232)

5- (3-ethoxy-3'-(methylamino)-[1,1'-biphenyl] -4-yl) -3,6-dihydro-7H- [1,2,3] triazolo [4,5- d] Pyrimidine-7-one is an N-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline using the procedure of Example 6. Prepared from. LCMS (ESI) = 363.2 [M + H] ⁺ .

Example 77: 5- (3- (cyclopentyloxy) -4- (7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)) Synthesis of phenyl) picolinic acid (Compound 233)

5- (3- (Cyclopentyloxy) -4- (7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl) phenyl) picolinic acid Was prepared from methyl 5-bromopicolinate using the procedures of Examples 42 and 9. LCMS (ESI) = 419.2 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ11.7 (road s, 1H), 9/11 (s, 1H), 8.38 (d, J = 8.4 Hz, 1H), 8.10-8 .18 (m, 1H), 8.14 (s, 1H), 8.03 (d, J = 7.8, 1H), 7.50-7.60 (m, 2H), 5.18-5 .28 (m, 1H), 1.80-2.00 (m, 4H), 1.55-1.75 (m, 4H).

Example 78: 3- (3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)- Synthesis of [1,1'-biphenyl] -3-yl) propionic acid (Compound 234)

3- (3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)-[1,1 '-Biphenyl] -3-yl) propionic acid was prepared from 3- (3-bromophenyl) propionic acid using the procedure of Example 42. LCMS (ESI) = 406.1 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ12.17 (s, 2H), 7.87 (d, J = 8.1 Hz, 1H), 7.69-7.56 (m, 2H), 7. 41 (d, J = 7.5Hz, 3H), 7.35-7.26 (m, 1H), 4.31 (q, J = 6.9Hz, 2H), 2.93 (t, J = 7) .7Hz, 2H), 2.68-2.52 (m, 2H), 1.40 (t, J = 6.9Hz, 3H).

Example 79: (E) -3- (3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5) -Il)-[1,1'-biphenyl] -3-yl) Synthesis of acrylic acid (Compound 235)

(E) -3- (3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)- [1,1'-Biphenyl] -3-yl) acrylic acid was prepared from (E) -3- (3-bromophenyl) acrylic acid using the procedure of Example 42. LCMS (ESI) = 404.1 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ8.12 (s, 1H), 7.92 (d, J = 8.1 Hz, 1H), 7.88-7.66 (m, 3H), 7. 56 (t, J = 7.7Hz, 1H), 7.49 (d, J = 8.1Hz, 2H), 6.72 (d, J = 16.0Hz, 1H), 4.34 (q, J) = 6.8Hz, 2H), 1.41 (t, J = 6.9Hz, 3H).

Example 80: (Z) -3- (3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5 -Il)-[1,1'-biphenyl] -3-yl) -2-methylacrylic acid (Compound 236) and (E) -3- (3'-ethoxy-4'-(7-oxo-6, 6) 7-Dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)-[1,1'-biphenyl] -3-yl) -2-methylacrylic acid (Compound 237) ) Synthesis

Step 1: In a 50 mL round bottom flask, 3-bromobenzaldehyde (1.84 g, 9.94 mmol, 1.00 eq) and methyl acrylate (1.84 g, 9.94 mmol, 1.00 eq) in dioxane (0.50 mL) and _H2O (0.50 mL). 2.57 g mg, 29.8 mmol, 3.00 eq) was added and DABCO (1.12 g, 9.94 mmol, 1.00 eq) was added. The resulting solution was stirred at room temperature for 14 hours. The residue was chromatographed on a silica gel column with ethyl acetate / petroleum ether (1:10). This gave 2.5 g (93%) of methyl 2-((3-bromophenyl) (hydroxy) methyl) acrylate as a colorless oil. ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ7.78-7.35 (m, 2H), 6.24 (t, J = 1.5Hz, 2H), 6.20 (s, 1H), 6. 02 (s, 1H), 5.88 (brs, 1H), 5.43 (d, J = 1.5Hz, 1H), 3.62 (s, 3H).

Step 2: Methyl 2-((3-bromophenyl) (hydroxy) methyl) acrylate (250 mg, 0.922 mmol, 1.00 eq) with THF (2.0 mL) and I2 (515 mg, 2.03 mmol, 2. 20 equivalents) was added. The resulting brown solution was cooled to 0 ° C. NaBH ₄ (69.8 mg, 1.84 mmol, 2.00 eq) was added in portions and the white suspension was stirred for 17 hours. The reaction was quenched by the addition of _H2O (5 ml) at 0 ° C. The resulting mixture was extracted with DCM (3x5 ml). The combined organic layer was washed with NaCl (5 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain methyl (E) -3- (3-bromophenyl) -2-acrylate (40 mg, 17%) as a yellow oil. ^{1 1} H NMR (300 MHz, CDCl ₃ ) δ7.63 (s, 1H), 7.55 (s, 1H), 7.48 (dt, J = 7.3, 1.9 Hz, 1H), 7.41- 7.23 (m, 2H), 3.85 (s, 3H), 2.13 (d, J = 1.5Hz, 3H).

Step 3: 5- (2-ethoxy-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2) in dioxane (1.0 mL) and _H2O (0.1 mL) -Il) Phenyl) -3- (4-Methylbenzyl) -3,6-dihydro-7H- [1,2,3] Triazolo [4,5-d] pyrimidin-7-one (94.7 mg, 0. K ₂ CO in a solution of 188 mmol (1.20 eq) and methyl (2E) -3- (3-bromophenyl) -2-methylprop-2-enoate (40.0 mg, 0.157 mmol, 1.00 eq). ₃ (65.0 mg, 0.470 mmol, 3.00 eq) and Pd (dpppf) Cl ₂ (11.5 mg, 0.016 mmol, 0.10 eq) were added. After stirring at 100 ° C. for 2 hours under a nitrogen atmosphere, the resulting mixture was concentrated under reduced pressure. By purifying the residue by silica gel column chromatography, methyl (E) -3- (3'-ethoxy-4'-(3- (4-methoxybenzyl) -7-oxo-6,7-) as a white solid is obtained. Dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)-[1,1'-biphenyl] -3-yl) -2-methyl acrylate (100 mg) rice field. LCMS (ESI) = 552.2 [M + H] ⁺ .

Step 4: Methyl (E) -3- (3'-ethoxy-4'-(3- (4-methoxybenzyl) -7-oxo-6,7-dihydro-3H) in trifluoroacetic acid (1.0 mL) -[1,2,3] triazolo [4,5-d] pyrimidin-5-yl)-[1,1'-biphenyl] -3-yl) -2-methyl acrylate (40.0 mg, 0.073 mmol) , 1.00 equivalent) was placed in an 8 mL vial. The resulting solution was stirred at 80 ° C. for 2 hours and then concentrated under reduced pressure. This resulted in 40 mg of methyl (E) -3- (3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5] as a yellow solid. -D] Pyrimidine-5-yl)-[1,1'-biphenyl] -3-yl) -2-methyl acrylate was obtained and continued without further purification. LCMS (ESI) = 432.2 [M + H] ⁺ .

Step 5: Methyl (E) -3- (3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4] in DMSO (1.0 mL)) , 5-d] Pyrimidine-5-yl)-[1,1'-biphenyl] -3-yl) -2-methyl acrylate (40.0 mg) in an 8 mL vial, followed by 2N NaOH (1). .0 mL) was added. The resulting solution was stirred at room temperature for 2 hours. The pH was adjusted to pH 6 by the addition of AcOH. By purifying the crude product by preparative HPLC, 1.6 mg (4.0%) of (Z) -3- (3'-ethoxy-4'-(7-oxo-6,7) as a white solid is obtained. -Dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)-[1,1'-biphenyl] -3-yl) -2-methylacrylic acid (peak 1) , And 8.3 mg (21%) of (E) -3- (3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] as a white solid. Triazolo [4,5-d] pyrimidin-5-yl)-[1,1'-biphenyl] -3-yl) -2-methylacrylic acid (peak 2) was obtained.

(Z) -3- (3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)- [1,1'-Biphenyl] -3-yl) -2-methylacrylic acid data: LCMS (ESI) = 418.0 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ11.02 (brs, 1H) 8.01 (d, J = 8.4 Hz, 1H), 7.81 (s, 1H), 7.59 (d, J) = 7.2Hz, 1H), 7.48-7.36 (m, 4H), 4.35-4.28 (m, 2H), 2.03 (d, J = 1.2Hz, 3H), 1 .44 (d, J = 6.9Hz, 3H).

(E) -3- (3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)- [1,1'-Biphenyl] -3-yl) -2-methylacrylic acid data: LCMS (ESI) = 418.0 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ8.00 (d, J = 8.1 Hz, 1H), 7.84 (s, 1H), 7.77 (d, J = 7.8 Hz, 1H), 7.72 (s, 1H), 7.60-7.51 (m, 2H), 7.44 (d, J = 6.9Hz, 2H), 4.33 (q, J = 6.9Hz, 2H) ), 2.10 (d, J = 1.2Hz, 3H), 1.43 (t, J = 6.6Hz, 3H).

Example 81: 3- (3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)- Synthesis of [1,1'-biphenyl] -3-yl) -2-methylpropanoic acid (Compound 238)

Methyl (E) -3- (3'-ethoxy-4'-(3- (4-methoxybenzyl) -7-oxo-6,7-dihydro-3H-] in MeOH (1.0 mL) , 3] Triazolo [4,5-d] pyrimidin-5-yl)-[1,1'-biphenyl] -3-yl) -2-methyl acrylate (60.0 mg, 0.109 mmol, 1.00 equivalent) ), Pd / C (10.0 mg) was added. Hydrogen was introduced by hydrogen balloon and the mixture was stirred at room temperature for 2 hours. The mixture was filtered through a Celite pad and concentrated under reduced pressure. As a result, as a white solid, methyl 3- (3'-ethoxy-4'-(3- (4-methoxybenzyl) -7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [1,2,3] 4,5-d] Pyrimidine-5-yl)-[1,1'-biphenyl] -3-yl) -2-methylpropanol (40 mg, 66%) was obtained. LCMS (ESI) = 554.3 [M + H] ⁺ .

3- (3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)-[1,1 '-Biphenyl] -3-yl) -2-methylpropionic acid was prepared using the procedures of Examples 6 and 9. LCMS (ESI) = 420.1 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ8.00 (d, J = 8.4 Hz, 1H), 7.61 (d, J = 1.8 Hz, 2H), 7.44-7.37 (m) , 3H), 7.24 (d, J = 7.5Hz, 1H), 4.33 (q, J = 6.9Hz, 2H), 3.05-2.96 (m, 1H), 2.77 -2.70 (m, 2H), 1.43 (t, J = 6.9Hz, 3H), 1.10 (d, J = 6.3Hz, 3H).

Example 82: 2-((3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)) -Synthesis of [1,1'-biphenyl] -3-yl) methyl) butanoic acid (Compound 239)

Step 1: LDA (2M) (4.74 mL) is added dropwise at −78 ° C. under N ₂ to a stirred solution of ethyl butyrate (1.00 g, 8.61 mmol, 1.00 eq) in THF (20 mL). did. The resulting mixture was stirred under N ₂ at −30 ° C. for 1.5 hours. To the above mixture was added dropwise 1-bromo-3- (bromomethyl) benzene (2.37 g, 9.47 mmol, 1.1 eq) at −30 ° C. over 15 minutes. The resulting mixture was stirred at −30 ° C. for an additional 3 hours. The reaction was quenched by the addition of 1 M HCl (20 mL) at 5 ° C. The resulting mixture was extracted with Et ₂ O (3 x 20 mL). The combined organic layer was washed with brine (2x20 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give ethyl 2- (3-bromobenzyl) butanoate (800 mg, 26.4%) as a white solid.

Step 2: Ethyl 2- (3-bromobenzyl) butanoate (800 mg, 2.80 mmol, 1.00 eq) and bis (pinacolat) diboron (1.42 g, 5.61 mmol, 2.0 eq), KOAc (551 mg, 551 eq, 5.61 mmol (2.0 eq), dioxane (10.0 mL), Pd (dpppf) Cl ₂ (205 mg, 0.281 mmol, 0.1 eq) were added to a 20 ml vial at room temperature. The resulting mixture was stirred at 100 ° C. for 2 hours, after which the resulting mixture was concentrated under reduced pressure. By purifying the residue by silica gel column chromatography, ethyl 2- (3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzyl) butanoate (3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzyl) as a white solid is obtained. 700 mg, 62%) was obtained.

2-((3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)-[1, 1'-biphenyl] -3-yl) methyl) butanoic acid was prepared using the procedures of Examples 1 and 9. LCMS (ESI) = 434.2 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ8.23 (d, J = 8.4 Hz, 1H), 7.55 (d, J = 9.0 Hz, 2H), 7.46-7.35 (m) , 1H), 7.40 (s, 2H), 7.28 (d, J = 7.6Hz, 1H), 4.41 (q, J = 7.0Hz, 2H), 3.02 (dd, J) = 13.6, 8.9Hz, 1H), 2.86 (dd, J = 13.6, 6.0Hz, 1H), 2.71-2.55 (m, 1H), 1.78-1. 53 (m, 4H), 1.00 (t, J = 7.4Hz, 3H).

Example 83: 2-((3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)) -Separation of enantiomers of [1,1'-biphenyl] -3-yl) methyl) butanoic acid (Compound 240 and Compound 241)

2-((3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)-[1, 1'-biphenyl] -3-yl) methyl) butanoic acid (racemic) (58 mg) is a chiral preparative HPLC (CHIRALPAK IC-3 column, 20 ^* 250 mm, 5 um; mobile phase, 20 mL / min. Phase A: n. -Hexan / DCM = 5/1, phase B: ethanol (0.1% TFA)) separated into individual enantiomers. As a result, as a white solid, (S) -2-((3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] ] Pyrimidine-5-yl)-[1,1'-biphenyl] -3-yl) methyl) butanoic acid (18 mg, 36%, ee% = 99.5%), and (R)-as a white solid. 2-((3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)-[1, 1'-biphenyl] -3-yl) methyl) butanoic acid (17.8 mg, 36%, ee% = 99.2%) was obtained.

Data for compound 240 (peak 1): LCMS (ESI) = 434.2 [M + H] ⁺ . HPLC (CHIRALPAK IC-3, 4.6x50mm, 3μm, 1.0 mL / min); A: n-hexane: DCM 5/1; B: EtOH w / 0.1% TFA; 25% B): t _R = 2.27 minutes. ^* The absolute stereochemistry of a single isolated enantiomer is not determined.

Data for compound 241 (peak 2): LCMS (ESI) = 434.2 [M + H] ⁺ . HPLC (CHIRALPAK IC-3, 4.6x50mm, 3μm, 1.0 mL / min; A: n-hexane / DCM, 5/1; B: EtOH w / 0.1% TFA; 25% B): t _R = 2.78 minutes. ^* The absolute stereochemistry of a single isolated enantiomer is not determined.

Example 84: Ethyl 3- (3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)) -Synthesis of [1,1'-biphenyl] -3-yl) -2,2-dimethylpropanoate (Compound 242)

Ethyl 3- (3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)-[1, 1'-biphenyl] -3-yl) -2,2-dimethylpropanoate was prepared from ethyl isobutyrate using the procedure of Example 82. LCMS (ESI) = 462.3 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ11.68 (s, 1H), 7.93 (d, J = 8.3 Hz, 1H), 7.63 (d, J = 7.9 Hz, 1H), 7.51-7.31 (m, 4H), 7.17 (d, J = 7.6Hz, 1H), 4.30 (q, J = 6.9Hz, 2H), 4.07 (q, J) = 7.1Hz, 2H), 2.92 (s, 2H), 1.41 (t, J = 6.9Hz, 3H), 1.18 (t, J = 7.1Hz, 3H), 1.16 (S, 6H).

Example 85: 3- (3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)- Synthesis of [1,1'-biphenyl] -3-yl) -2,2-dimethylpropanoic acid (Compound 243)

3- (3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)-[1,1 '-Biphenyl] -3-yl) -2,2-dimethylpropanoic acid was prepared using the ester hydrolysis procedure of Example 9. LCMS (ESI) = 434.2 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ7.98 (d, J = 8.4 Hz, 1H), 7.62 (d, J = 7.7 Hz, 1H), 7.53 (s, 1H), 7.46-7.31 (m, 3H), 7.21 (d, J = 7.5Hz, 1H), 4.31 (q, J = 6.8Hz, 2H), 2.90 (s, 2H) ), 1.42 (t, J = 6.9Hz, 3H), 1.13 (s, 6H).

Example 86: 1-((3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)) -Synthesis of [1,1'-biphenyl] -3-yl) methyl) cyclopropane-1-carboxylic acid (Compound 244)

1-((3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)-[1, The 1'-biphenyl] -3-yl) methyl) cyclopropane-1-carboxylic acid was prepared from tert-butylcyclopropanecarboxylate using the procedures of Examples 82 and 58. LCMS (ESI) = 433.2 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ7.96 (d, J = 8.5 Hz, 1H), 7.65 (t, J = 1.7 Hz, 1H), 7.59 (dt, J = 7) .7, 1.6Hz, 1H), 7.46-7.29 (m, 4H), 4.31 (q, J = 6.9Hz, 2H), 2.98 (s, 2H), 1.42 (T, J = 6.9Hz, 3H), 1.15 (q, J = 3.7Hz, 2H), 0.89 (q, J = 3.9Hz, 2H).

Example 87: Ethyl 1-((3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl) )-[1,1'-Biphenyl] -3-yl) Methyl) Cyclobutane-1-carboxylate (Compound 245)

Ethyl 1-((3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)-[1 , 1'-biphenyl] -3-yl) methyl) cyclobutane-1-carboxylate was prepared using the procedure of Example 82. LCMS (ESI) = 474.3 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ12.07 (s, 1H), 7.89 (d, J = 8.2 Hz, 1H), 7.63 (d, J = 7.8 Hz, 1H), 7.50 (s, 1H), 7.47-7.32 (m, 3H), 7.19 (d, J = 7.4Hz, 1H), 4.30 (q, J = 6.9Hz, 2H) ), 4.08 (q, J = 7.1Hz, 2H), 3.17 (s, 2H), 2.40-2.28 (m, 2H), 2.16-2.02 (m, 2H) ), 1.99-1.72 (m, 2H), 1.41 (t, J = 6.9Hz, 3H), 1.15 (t, J = 7.1Hz, 3H).

Example 88: 1-((3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)) -Synthesis of [1,1'-biphenyl] -3-yl) methyl) cyclobutane-1-carboxylic acid (Compound 246)

1-((3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)-[1, The 1'-biphenyl] -3-yl) methyl) cyclobutane-1-carboxylic acid was prepared using the ester hydrolysis procedure of Example 9. LCMS (ESI) = 446.2 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ7.93 (d, J = 8.2 Hz, 1H), 7.61 (d, J = 7.9 Hz, 1H), 7.54 (s, 1H), 7.46-7.32 (m, 3H), 7.24 (d, J = 7.7Hz, 1H), 4.31 (q, J = 6.9Hz, 2H), 3.15 (s, 2H) ), 2.39-2.22 (m, 2H), 2.12-1.97 (m, 2H), 1.96-1.71 (m, 2H), 1.42 (t, J = 6) .9Hz, 3H.

Example 89: 2-((3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)) -Synthesis of [1,1'-biphenyl] -3-yl) oxy) butanoic acid (Compound 247)

Methyl 2- (3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenoxy) butanoate in dioxane (0.50 mL) and _H2O (0.10 mL) (Prepared from methyl 2-bromobutanoate using the method of Example 56) (50.0 mg, 0.156 mmol, 1.00 eq) and 5- (4-bromo-2-ethoxyphenyl) In a solution of -3,6-dihydro-7H- [1,2,3] triazolo [4,5-d] pyrimidin-7-one (52.5 mg, 0.156 mmol, 1.00 eq), K ₂ CO ₃ (64.8 mg, 0.468 mmol, 3.00 eq) and Pd (dpppf) Cl ₂ (11.4 mg, 0.011 mmol, 0.10 eq) were added. After stirring at 100 ° C. for 16 hours under a nitrogen atmosphere, the resulting mixture was concentrated under reduced pressure. The crude product is purified by preparative HPLC to give 2-((3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3]) as an off-white solid. Triazolo [4,5-d] pyrimidin-5-yl)-[1,1'-biphenyl] -3-yl) oxy) butanoic acid (15.7 mg, 23%) was obtained. LCMS (ESI) = 436.1 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ12.05 (s, 1H), 7.88 (d, J = 8.4 Hz, 1H), 7.38 (dt, J = 11.0, 6.9 Hz) , 4H), 7.26 (s, 1H), 6.95 (d, J = 8.1Hz, 1H), 4.83 (t, J = 6.0Hz, 1H), 4.31 (q, J) = 6.9Hz, 2H), 2.00-1.85 (m, 2H), 1.40 (t, J = 6.9Hz, 3H), 1.05 (t, J = 7.4Hz, 3H) ..

Example 90: 2-((3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)) -Synthesis of [1,1'-biphenyl] -3-yl) oxy) pentanic acid (Compound 248)

2-((3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)-[1, 1'-biphenyl] -3-yl) oxy) pentanoic acid was prepared using the procedure of Example 89. LCMS (ESI) = 450.2 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ12.20 (s, 1H), 7.86 (d, J = 8.2 Hz, 1H), 7.48-7.31 (m, 4H), 7. 26 (s, 1H), 6.94 (d, J = 8.1Hz, 1H), 4.87 (t, J = 6.3Hz, 1H), 4.31 (q, J = 6.9Hz, 2H) ), 1.89 (q, J = 7.0Hz, 2H), 1.52 (q, J = 7.7Hz, 2H), 1.40 (t, J = 6.9Hz, 3H), 0.96 (T, J = 7.3Hz, 3H).

Example 91: 2-((3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)) -Synthesis of [1,1'-biphenyl] -3-yl) oxy) -2-phenylacetic acid (Compound 249)

2-((3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)-[1, 1'-biphenyl] -3-yl) oxy) -2-phenylacetic acid was prepared from ethyl2-bromo-2-phenylacetate using the procedure of Example 89. LCMS (ESI) = 484.2 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ7.93 (d, J = 8.0 Hz, 1H), 7.66-7.57 (m, 2H), 7.47-7.29 (m, 8H) ), 7.05-6.96 (m, 1H), 5.82 (s, 1H), 4.31 (q, J = 6.9Hz, 2H), 1.41 (t, J = 6.9Hz) , 3H).

Example 92: 2-((3'-(cyclopentyloxy) -4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5) -Il)-[1,1'-biphenyl] -3-yl) Oxy) Propionic acid (Compound 250) synthesis

2-((3'-(Cyclopentyloxy) -4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)- [1,1'-biphenyl] -3-yl) oxy) propionic acid was prepared using the procedure of Example 89. 462.2 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ8.02 (d, J = 8.4 Hz, 1H), 7.46-7.33 (m, 3H), 7.33 (d, J = 7.7 Hz) , 1H), 7.23 (t, J = 2.1Hz, 1H), 6.93 (ddd, J = 8.1,2.6,1.1Hz, 1H), 5.25-5.18 ( m, 1H), 4.94 (d, J = 7.5Hz, 1H), 2.02-1.80 (m, 4H), 1.79-1.59 (m, 4H), 1.54 ( d, J = 6.7 Hz, 3H).

Example 93: (R) -2-((3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-) 5-Il)-[1,1'-biphenyl] -3-yl) Oxy) Propionic acid (Compound 251) synthesis

Step 1: 3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenol (1.00 g, 4.54 mmol, 1.00 eq) in THF (10 mL) , Methyl (S) -2-hydroxypropanoate (0.52 g, 5.00 mmol, 1.10 eq), and PPh ₃ (1.55 g, 5.90 mmol, 1.30 eq) in a stirred solution of N. DIAD (1.19 g, 5.91 mmol, 1.30 eq) was added dropwise at 0 ° C. under ₂ atmospheres. The resulting mixture was stirred at room temperature for 16 hours and then concentrated under reduced pressure. By purifying the residue by silica gel column chromatography, methyl (R) -2- (3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) as off-white oil) Phenoxy) propanoate (500 mg, 36%) was obtained. LCMS (ESI) = 307.2 [M + H] ⁺ .

Step 2: Methyl (R) -2- (3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-) in dioxane (1.0 mL) and _H2O (0.3 mL) 2-yl) phenoxy) propanoate (90.0 mg, 0.294 mmol, 1.00 eq) and 5- (4-bromo-2-ethoxyphenyl) -3,6-dihydro-7H- [1,2,3] In a solution of triazolo [4,5-d] pyrimidin-7-one (98.8 mg, _0.294 mmol, 1.0 eq), K2 _CO3 (122 mg, 0.882 mmol, 3.00 eq) and Pd ( dppf) Cl ₂ (21.5 mg, 0.029 mmol, 0.1 eq) was added dropwise. After stirring at 100 ° C. for 16 hours under a nitrogen atmosphere, the resulting mixture was concentrated under reduced pressure. By purifying the residue by preparative HPLC, as an off-white solid, (R) -2-((3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H-] 1,2, 3] Triazolo [4,5-d] pyrimidin-5-yl)-[1,1'-biphenyl] -3-yl) oxy) propionic acid (15.7 mg, 13%) was obtained. LCMS (ESI) = 422.1 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ7.97 (d, J = 8.5 Hz, 1H), 7.40-7.25 (m, 4H), 7.21 (d, J = 2.2 Hz) , 1H), 6.89 (dd, J = 8.7, 1.9Hz, 1H), 4.77 (d, J = 6.9Hz, 1H), 4.31 (q, J = 7.0Hz, 2H), 1.49 (d, J = 6.7Hz, 3H), 1.42 (t, J = 6.9Hz, 3H). Analytical Chiral HPLC: CHIRALPAK AD-3 Column [100 ^* 3 mm, 3 μm, 1.5 mL / min, 50% Hexane: DCM (5: 1) -100% EtOH] (w / 0.1% TFA): t _R 2.01 minutes (peak 1).

Example 94: (S) -2-((3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-) 5-Il)-[1,1'-biphenyl] -3-yl) Oxy) Propionic acid (Compound 252) synthesis

(S) -2-((3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)) -[1,1'-biphenyl] -3-yl) oxy) propanoic acid was prepared from methyl (R) -2-hydroxypropanoate using the procedure of Example 89. LCMS (ESI) = 422.1 [M + H] ⁺ . Analytical Chiral HPLC: CHIRALPAK AD-3 Column [100 ^* 3 mm, 3 μm, 1.5 mL / min, 50% Hexane: DCM (5: 1) -100% EtOH] (w / 0.1% TFA) t _R 3.48 minutes (peak 2).

Example 95: (R) -2-((3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-) 5-yl)-[1,1'-biphenyl] -3-yl) oxy) butanoic acid (Compound 253) and (S) -2-((3'-ethoxy-4'-(7-oxo-6, 6) 7-Dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)-[1,1'-biphenyl] -3-yl) oxy) butanoic acid (Compound 254) Synthetic.

2-((3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)-[1, 1'-biphenyl] -3-yl) oxy) butanoic acid is CHIRALPAK IC-3 column, 20 ^* 250 mm, 5 μM. A: n-hexane / DCM, 5/1. B: EtOH w / 0.1% TFA, 20% B was used to purify individual enantiomers.

(R) -2-((3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)) -[1,1'-biphenyl] -3-yl) oxy) butanoic acid (peak 1) data: LCMS (ESI) = 436.1 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ12.21 (s, 1H), 7.86 (d, J = 8.5 Hz, 1H), 7.48-7.31 (m, 4H), 7. 26 (t, J = 2.1Hz, 1H), 6.99-6.90 (m, 1H), 4.84 (dd, J = 6.8, 5.2Hz, 1H), 4.31 (q) , J = 7.0Hz, 2H), 2.02-1.85 (m, 2H), 1.39 (t, J = 6.9Hz, 3H), 1.04 (t, J = 7.4Hz, 3H). Analytical chiral SFC: CHIRALPAK AD-3; 100 ^* 3.0 mm, 3 μm, EtOH (0.2% MSA), 1.5 mL / min; Pump B: 50.0%, t _R = 1.51 min.

(S) -2-((3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)) -[1,1'-biphenyl] -3-yl) oxy) butanoic acid (peak 2) data: LCMS (ESI) = 436.1 [M + H] ⁺ . Chiral SFC: CHIRALPAK AD-3; 100 ^* 3.0 mm, 3 μm, EtOH (0.2% MSA), 1.5 mL / min; Pump B: 50.0%, t _R = 3.94 min.

Example 96A: (R) -2-((3'-ethoxy-5-hydroxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-] d] Pyrimidine-5-yl)-[1,1'-biphenyl] -3-yl) Oxy) Propionic acid (Compound 255) synthesis

(R) -2-((3'-ethoxy-5-hydroxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-) 5-yl)-[1,1'-biphenyl] -3-yl) oxy) propanoic acid is methyl (R) -2- (3-bromo) using the procedures of Examples 93, 42, and 9. -5-Hydroxyphenoxy) Prepared from propanoate. LCMS (ESI) = 438.1 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ9.65 (s, 1H), 7.93 (d, J = 8.2 Hz, 1H), 7.31-7.22 (m, 2H), 6. 68 (d, J = 7.7Hz, 2H), 6.32 (s, 1H), 4.82-4.70 (m, 1H), 4.29 (q, J = 6.8Hz, 2H), 1.49 (d, J = 6.7Hz, 3H), 1.41 (t, J = 6.9Hz, 3H). Analytical Chiral HPLC: CHIRALPAK AD-3 (100x3 mm, 3 μm, 1.5 mL / min; A: n-hexane / DCM, 5/1; B: EtOH w / 0.1% TFA; 30% B): t _R = 1.96 minutes (peak 1).

Example 96B: (S) -2-((3'-ethoxy-5-hydroxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-] d] Pyrimidine-5-yl)-[Synthesis of 1,1 "-biphenyl] -3-yl) Oxy) Propionic acid (Compound 256)

(S) -2-((3'-ethoxy-5-hydroxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-) 5-yl)-[1,1'-biphenyl] -3-yl) oxy) propionic acid is methyl (S) -2- (3-bromo-5-hydroxyphenoxy) using the procedure of Example 96A. ) Prepared from propanoate. LCMS (ESI) = 438.1 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ9.65 (s, 1H), 7.93 (d, J = 8.2 Hz, 1H), 7.31-7.22 (m, 2H), 6. 68 (d, J = 7.7Hz, 2H), 6.32 (s, 1H), 4.82-4.70 (m, 1H), 4.29 (q, J = 6.8Hz, 2H), 1.49 (d, J = 6.7Hz, 3H), 1.41 (t, J = 6.9Hz, 3H). Analytical Chiral HPLC: CHIRALPAK AD-3 (100x3 mm, 3 μm, 1.5 mL / min; A: n-hexane / DCM, 5/1; B: EtOH w / 0.1% TFA; 30% B): t _R = 2.68 minutes (peak 2).

Example 97: 2-((3'-ethoxy-5-hydroxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-) Synthesis of 5-yl)-[1,1'-biphenyl] -3-yl) oxy) oxyacid (compound 257)

2-((3'-ethoxy-5-Hydroxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)) -[1,1'-biphenyl] -3-yl) oxy) butanoic acid, methyl 2-bromobutanoate and 5-bromobenzene-1,3-diol using the procedures of Examples 42 and 9. Prepared from. LCMS (ESI) = 452.1 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ7.93 (d, J = 8.4 Hz, 1H), 7.31-7.22 (m, 2H), 6.68 (dt, J = 9.3) , 1.8Hz, 2H), 6.35 (t, J = 2.1Hz, 1H), 4.38 (dd, J = 7.1, 5.1Hz, 1H), 4.28 (q, J = 6.9Hz, 2H), 3.17 (s, 2H), 1.82 (dp, J = 14.0, 7.1Hz, 2H), 1.40 (t, J = 6.9Hz, 3H), 1.03 (d, J = 24.0Hz, 8H).

Example 98: (R) -2-((3'-ethoxy-5-hydroxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-] d] Synthesis of pyrimidine-5-yl)-[1,1'-biphenyl] -3-yl) oxy) butanoic acid (Compound 258)

(R) -2-((3'-ethoxy-5-hydroxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-) 5-Il)-[1,1'-biphenyl] -3-yl) oxy) oxy) butanoate is methyl (S) -2-hydroxybutanoate using the procedures of Examples 93, 42, and 9. And 5-bromobenzene-1,3-diol was prepared. LCMS (ESI) = 452.1 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ9.72 (s, 1H), 7.91 (d, J = 8.4 Hz, 1H), 7.33-7.24 (m, 2H), 6. 70 (dt, J = 9.6, 1.7Hz, 2H), 6.34 (t, J = 2.1Hz, 1H), 4.61 (t, J = 6.2Hz, 1H), 4.29 (Q, J = 6.9Hz, 2H), 1.97-1.77 (m, 2H), 1.40 (t, J = 6.9Hz, 3H), 1.02 (t, J = 7. 4Hz, 3H). Analytical Chiral HPLC: CHIRALPAK ID-3 (50 ^* 4.6 mm, 3 μm, 1 mL / min; A: Hexane / DCM, 5/1; B: EtOH w / 0.1% TFA; 50% B): t _R = 1.57 minutes (peak 1).

Example 99: (S) -2-((3'-ethoxy-5-hydroxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-] d] Synthesis of pyrimidine-5-yl)-[1,1'-biphenyl] -3-yl) oxy) butanoic acid (Compound 259)

(S) -2-((3'-ethoxy-5-hydroxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-) 5-Il)-[1,1'-biphenyl] -3-yl) oxy) butanoic acid was prepared by preparative chiral HPLC using a CHIRALPAK IC-3 column using the procedure of Example 95. LCMS (ESI) = 452.1 [M + H] ⁺ . Analytical Chiral HPLC: CHIRALPAK ID-3 (50 ^* 4.6 mm, 3 um, 1 mL / min); A: Hexane / DCM, 5/1; B: EtOH w / 0.1% TFA; 50% B. t _R 2.43 = minutes (peak 2).

Example 100: (R) -2-((3'-ethoxy-4,5-difluoro-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,] 5-d] Pyrimidine-5-yl)-[1,1'-biphenyl] -3-yl) Oxy) Synthesis of propanoic acid (Compound 260)

Step 1: 5-bromo-2,3-difluorophenol (500 mg, 2.32 mmol, 1.00 eq), methyl (S) -2-hydroxypropanoate (479 mg, 2.87 mmol, 1.2 eq),. PPh ₃ (816 mg, 3.11 mmol, 1.3 eq) and THF (10 mL) were added to a 50 ml round bottom flask. DIAD (629 mg, 3.11 mmol, 1.3 eq) was added to the above mixture at 0 ° C. over 15 minutes. The resulting mixture was stirred at room temperature for an additional 12 hours, after which the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give methyl (R) -2- (5-bromo-2-2,3-difluorophenoxy) propanoate (450 mg, 58%) as a yellow oil. ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ7.37 (ddd, J = 9.7, 6.3, 2.3 Hz, 1H), 7.23 (dt, J = 6.7, 2.2 Hz, 1H), 5.33-5.11 (m, 1H), 3.70 (s, 3H), 1.54 (d, J = 6.8Hz, 3H).

Step 2: Methyl (R) -2- (5-bromo-2,3-difluorophenoxy) propanoate (300 mg, 1.02 mmol, 1.00 eq) and bis (pinacolat) diboron (310 mg, 1.22 mmol, 1. 2 equivalents), KOAc (299 mg, 3.05 mmol, 3.0 equivalents), dioxane (6.0 mL), Pd (dpppf) Cl ₂ (74.4 mg, 0.102 mmol, 0.10 equivalents) in a 40 ml vial. The addition was made and the resulting mixture was stirred at 100 ° C. for 2 hours. By purifying the mixture by silica gel column chromatography, methyl (R) -2- (2,3-difluoro-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane) as a yellow oil is obtained. -2-yl) Phenoxy) propanoate (350 mg, 92%) was obtained.

(R) -2-((3'-ethoxy-4,5-difluoro-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d]] Pyrimidine-5-yl)-[1,1'-biphenyl] -3-yl) oxy) propionic acid was prepared using the procedure of Example 89. LCMS (ESI) = 458.0 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ7.89 (d, J = 7.9 Hz, 1H), 7.42 (ddd, J = 11.6, 6.7, 2.0 Hz, 1H), 7 .39-7.29 (m, 2H), 7.20 (d, J = 6.9Hz, 1H), 5.02 (d, J = 7.0Hz, 1H), 4.28 (tt, J = 7.0, 3.9Hz, 2H), 1.52 (d, J = 6.7Hz, 3H), 1.39 (t, J = 6.9Hz, 3H). Analytical Chiral HPLC: CHIRALPAK IC-3 (50 ^* 4.6 mm, 3 μm, 1 mL / min; A: n-hexane / DCM, 5/1; B: EtOH w / 0.1% TFA), 15% B.I. t _R = 1.72 minutes (peak 1).

Example 101: (S) -2-((3'-ethoxy-4,5-difluoro-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,] 5-d] Pyrimidine-5-yl)-[1,1'-biphenyl] -3-yl) Oxy) Propionic acid (Compound 261) synthesis

(S) -2-((3'-ethoxy-4,5-difluoro-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d]] Pyrimidine-5-yl)-[1,1'-biphenyl] -3-yl) oxy) propanoic acid is prepared from methyl (R) -2-hydroxypropanoate using the procedure of Example 100. rice field. LCMS (ESI) = 458.0 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ7.88 (d, J = 8.0 Hz, 1H), 7.42 (ddd, J = 11.5, 6.6, 1.9 Hz, 1H), 7 .39-7.29 (m, 2H), 7.20 (d, J = 6.9Hz, 1H), 5.01 (q, J = 6.7Hz, 1H), 4.28 (qd, J = 7.0, 1.8Hz, 2H), 1.52 (d, J = 6.7Hz, 3H), 1.38 (t, J = 6.9Hz, 3H). Analytical Chiral HPLC: CHIRALPAK IC-3 (50 ^* 4.6 mm, 3 μm, 1 mL / min; A: n-hexane / DCM, 5/1; B: EtOH w / 0.1% TFA); 15% B) .. t _R = 3.79 minutes (peak 2).

Example 102: (R) -2-((3'-ethoxy-5-fluoro-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-] d] Pyrimidine-5-yl)-[Synthesis of 1,1 "-biphenyl] -3-yl) Oxy) Propionic acid (Compound 262)

(R) -2-((3'-ethoxy-5-fluoro-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidine-) 5-Il)-[1,1'-biphenyl] -3-yl) oxy) propionic acid was prepared using the procedure of Example 100. LCMS (ESI) = 440.0 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ7.93 (d, J = 8.5 Hz, 1H), 7.43-7.35 (m, 2H), 7.21 (dt, J = 9.9) , 1.9Hz, 1H), 7.12 (t, J = 1.9Hz, 1H), 6.77 (dt, J = 11.0, 2.2Hz, 1H), 4.89 (d, J = 7.0Hz, 1H), 4.32 (q, J = 6.9Hz, 2H), 1.51 (d, J = 6.7Hz, 3H), 1.40 (t, J = 6.9Hz, 3H) ). Analytical Chiral HPLC: CHIRALPAK IA-3 (50 ^* 4.6 mm, 3 μm, 1 mL / min); A: n-hexane / DCM, 5/1; B: EtOH w / 0.1% TFA, 50% B) .. t _R = 0.923 minutes (peak 1).

Example 103: (S) -2-((3'-ethoxy-5-fluoro-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-] d] Pyrimidine-5-yl)-[1,1'-biphenyl] -3-yl) Oxy) Propionic acid (Compound 263) synthesis

(S) -2-((3'-ethoxy-5-fluoro-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidine-) 5-Il)-[1,1'-biphenyl] -3-yl) oxy) propionic acid was prepared using the procedure of Example 100. LCMS (ESI) = 440.2 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ7.93 (d, J = 8.5 Hz, 1H), 7.43-7.35 (m, 2H), 7.21 (dt, J = 9.9) , 1.9Hz, 1H), 7.12 (t, J = 1.9Hz, 1H), 6.77 (dt, J = 11.0, 2.2Hz, 1H), 4.89 (d, J = 7.0Hz, 1H), 4.32 (q, J = 6.9Hz, 2H), 1.51 (d, J = 6.7Hz, 3H), 1.40 (t, J = 6.9Hz, 3H) ). Analytical Chiral HPLC: CHIRALPAK IA-3 (50 ^* 4.6 mm, 3 μm, 1 mL / min; A: n-hexane / DCM, 5/1; B: EtOH w / 0.1% TFA, 50% B). t _R = 1.23 minutes (peak 2).

Example 104: (R) -2-((3'-ethoxy-4-fluoro-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-] d] Pyrimidine-5-yl)-[1,1'-biphenyl] -3-yl) Oxy) Propionic acid (Compound 264) synthesis

(R) -2-((3'-ethoxy-4-fluoro-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-) 5-Il)-[1,1'-biphenyl] -3-yl) oxy) propionic acid was prepared using the procedure of Example 100. LCMS (ESI) = 440.2 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ7.94 (d, J = 8.0 Hz, 1H), 7.29 (ddd, J = 10.1, 5.1, 3.1 Hz, 5H), 4 .80 (q, J = 6.7Hz, 1H), 4.35-4.20 (m, 2H), 1.49 (d, J = 6.7Hz, 3H), 1.40 (t, J = 6.9Hz, 3H).

Example 105: (S) -2-((3'-ethoxy-4-fluoro-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-] d] Pyrimidine-5-yl)-[1,1'-biphenyl] -3-yl) Oxy) Propionic acid (Compound 265) synthesis

(S) -2-((3'-ethoxy-4-fluoro-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidine-) 5-Il)-[1,1'-biphenyl] -3-yl) oxy) propionic acid was prepared using the procedure of Example 100. LCMS (ESI) = 440. 2 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ7.91 (d, J = 7.9 Hz, 1H), 7.38-7.25 (m, 5H), 4.94 (q, J = 6.6 Hz) , 1H), 4.27 (qd, J = 6.8, 2.2Hz, 2H), 1.51 (d, J = 6.6Hz, 3H), 1.39 (t, J = 6.9Hz, 2H).

Example 106: (R) -2-((3'-ethoxy-5-methyl-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-] d] Pyrimidine-5-yl)-[1,1'-biphenyl] -3-yl) Oxy) Propionic acid (Compound 266) synthesis

(R) -2-((3'-ethoxy-5-methyl-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-) 5-Il)-[1,1'-biphenyl] -3-yl) oxy) propanoic acid was prepared from methyl (S) -2-hydroxypropanoate using the procedure of Example 100. LCMS (ESI) = 436.1 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ7.96 (d, J = 8.2 Hz, 1H), 7.38-7.30 (m, 2H), 7.15 (s, 1H), 7. 02 (s, 1H), 6.73 (s, 1H), 4.83 (s, 1H), 4.31 (q, J = 6.8Hz, 2H), 2.35 (s, 3H), 1 .50 (d, J = 6.6Hz, 3H), 1.42 (t, J = 6.9Hz, 3H).

Example 107: (S) -2-((3'-ethoxy-5-methyl-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-] d] Pyrimidine-5-yl)-[1,1'-biphenyl] -3-yl) Oxy) Propionic acid (Compound 267) synthesis

(S) -2-((3'-ethoxy-5-methyl-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-) 5-Il)-[1,1'-biphenyl] -3-yl) oxy) propanoic acid was prepared from methyl (R) -2-hydroxypropanoate using the procedure of Example 100. LCMS (ESI) = 436.1 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ7.96 (d, J = 8.2 Hz, 1H), 7.38-7.30 (m, 2H), 7.15 (s, 1H), 7. 02 (s, 1H), 6.73 (s, 1H), 4.83 (s, 1H), 4.31 (q, J = 6.8Hz, 2H), 2.35 (s, 3H), 1 .50 (d, J = 6.6Hz, 3H), 1.42 (t, J = 6.9Hz, 3H).

Example 108: Ethyl 2-((3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl) )-[1,1'-Biphenyl] -3-yl) Oxy) -3-Methylbutanoate (Compound 268)

Ethyl 2-((3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)-[1 , 1'-biphenyl] -3-yl) oxy) -3-methylbutanoate was prepared using the procedure of Example 56. LCMS (ESI) = 478.3 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ12.22 (s, 1H), 7.86 (d, J = 8.5 Hz, 1H), 7.48-7.33 (m, 4H), 7. 29-7.22 (m, 1H), 6.94 (ddd, J = 7.9, 2.6, 1.4Hz, 1H), 4.77 (d, J = 5.2Hz, 1H), 4 .31 (q, J = 6.9Hz, 2H), 4.17 (q, J = 7.0Hz, 2H), 2.24 (dt, J = 11.9, 6.7Hz, 1H), 1. 39 (t, J = 6.9Hz, 3H), 1.18 (t, J = 7.1Hz, 3H), 1.05 (dd, J = 6.8, 2.9Hz, 6H).

Example 109: 2-((3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)) -Synthesis of [1,1'-biphenyl] -3-yl) oxy) -3-methylbutanoic acid (Compound 269)

2-((3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)-[1, 1'-biphenyl] -3-yl) oxy) -3-methylbutanoic acid was prepared using the procedure of Example 56. LCMS (ESI) = 450.2 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ7.98 (d, J = 7.9 Hz, 1H), 7.34 (q, J = 4.8 Hz, 3H), 7.26 (d, J = 7) .7Hz, 1H), 7.19 (s, 1H), 6.92-6.83 (m, 1H), 4.32 (t, J = 7.0Hz, 1H), 4.26 (s, 2H) ), 2.17 (s, 1H), 1.41 (t, J = 6.9Hz, 3H), 1.01 (dd, J = 6.8, 2.6Hz, 6H).

Example 110: Ethyl 2-((3'-(cyclopentyloxy) -4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-) Synthesis of 5-yl)-[1,1'-biphenyl] -3-yl) oxy) acetate (Compound 270)

Ethyl 2-((3'-(cyclopentyloxy) -4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)) -[1,1'-biphenyl] -3-yl) oxy) acetate was prepared using the procedure of Example 56. LCMS (ESI) = 476.2 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ12.06 (s, 1H), 7.93 (d, J = 8.4 Hz, 1H), 7.49-7.33 (m, 4H), 7. 29 (t, J = 2.1Hz, 1H), 7.01 (ddd, J = 8.0, 2.5, 1.2Hz, 1H), 5.21 (tt, J = 5.6, 2. 6Hz, 1H), 4.91 (s, 2H), 4.19 (q, J = 7.1Hz, 2H), 2.55-2.46 (m, 1H), 1.96 (tt, J = 9.2,4.6Hz, 2H), 1.91-1.78 (m, 2H), 1.66 (ddt, J = 21.5, 11.0, 3.7Hz, 4H), 1.23 (T, J = 7.1Hz, 3H).

Example 111: Isopropyl2-((3'-(cyclopentyloxy) -4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-) Synthesis of 5-yl)-[1,1'-biphenyl] -3-yl) oxy) acetate (Compound 271)

Isopropyl2-((3'-(cyclopentyloxy) -4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)) -[1,1'-biphenyl] -3-yl) oxy) acetate was prepared using the procedure of Example 56. LCMS (ESI) = 490.3 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ12.07 (s, 1H), 7.92 (d, J = 8.4 Hz, 1H), 7.49-7.33 (m, 4H), 7. 28 (t, J = 2.0Hz, 1H), 7.00 (ddd, J = 8.0, 2.6, 1.2Hz, 1H), 5.21 (dt, J = 5.6, 2. 9Hz, 1H), 5.02 (hept, J = 6.2Hz, 1H), 4.87 (s, 2H), 2.03-1.89 (m, 2H), 1.89-1.78 ( m, 2H), 1.76-1.55 (m, 2H), 1.23 (d, J = 6.3Hz, 6H).

Example 112: 2-((3'-ethoxy-4-methyl-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-) Synthesis of 5-yl)-[1,1'-biphenyl] -3-yl) oxy) butanoic acid (Compound 272)

2-((3'-ethoxy-4-methyl-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)) -[1,1'-biphenyl] -3-yl) oxy) butanoate is prepared from 5-bromo-2-methylphenol and ethyl2-bromobutanoate using the procedures of Examples 42 and 9. rice field. LCMS (ESI) = 450.2 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ7.91 (d, J = 8.4 Hz, 1H), 7.36-7.19 (m, 4H), 7.10 (s, 1H), 4. 84 (s, 1H), 4.34-4.20 (m, 2H), 2.25 (s, 3H), 2.03-1.84 (m, 2H), 1.40 (t, J = 6.9Hz, 3H), 1.06 (t, J = 7.4Hz, 3H).

Example 113: 5- (3- (cyclopentyloxy) -4'-(1H-tetrazole-5-yl)-[1,1'-biphenyl] -4-yl) -3,6-dihydro-7H- [ 1,2,3] Synthesis of triazolo [4,5-d] pyrimidin-7-one (Compound 273)

3'-(Cyclopentyloxy) -4'-(3- (4-Methoxybenzyl) -7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin- 5-yl)-[1,1'-biphenyl] -4-carbonitrile is carried out from 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzonitrile. Prepared using the procedure of Example 6. 3'-(cyclopentyloxy) -4'-(3- (4-methoxybenzyl) -7-oxo-6,7-dihydro-3H- [1] in DMF (1.0 mL) and toluene (1.0 mL) , 2,3] Triazolo [4,5-d] pyrimidin-5-yl)-[1,1'-biphenyl] -4-carbonitrile (139 mg, 0.268 mmol, 1.00 equivalent) in an 8 mL vial. I put it in. Triethylamine Hydrochloride (92.2 mg, 0.670 mmol, 2.50 eq) and sodium azide (43.6 mg, 0.670 mmol, 2.50 eq) were added and the resulting solution was at 110 ° C. for 17 hours. Stirred. The reaction was quenched by the addition of 5 mL of water and the pH value of the solution was adjusted to 6 with 1 M HCl. By collecting the solids by filtration and drying them under a heating lamp, 50 mg (33%) of 5- (3- (cyclopentyloxy) -4'-(1H-tetrazole-5-yl)-"as gray solids- [1,1'-biphenyl] -4-yl) -3- (4-methoxybenzyl) -3,6-dihydro-7H- [1,2,3] triazolo [4,5-d] pyrimidine-7- Got on. LCMS (ESI) = 562.3 [M + H] ⁺ .

5- (3- (Cyclopentyloxy) -4'-(1H-tetrazole-5-yl)-[1,1'-biphenyl] -4-yl) -3,6-dihydro-7H- [1,2, 3] Triazolo [4,5-d] pyrimidin-7-one was prepared using the procedure of Example 6. LCMS (ESI) = 442.2 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ12.00 (s, 1H), 8.13 (d, J = 8.4 Hz, 2H), 7.98 (d, J = 8.4 Hz, 1H), 8.13 (d, J = 8.7Hz, 2H), 7.49 (d, J = 7.8Hz, 2H), 5.25-5.23 (m, 1H), 2.02-1.97 (M, 2H), 1.93-1.84 (m, 2H), 1.79-1.65 (m, 4H).

Example 114: (S) -2-amino-3- (3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] ] Pyrimidine-5-yl)-[1,1'-biphenyl] -3-yl) Propionic acid (Compound 274) synthesis

(S) -2-Amino-3- (3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5 -Il)-[1,1'-biphenyl] -3-yl) propanoic acid is (S) -3- (3-bromophenyl) -2-((tert-butoxycarbonyl) amino) propanoic acid, and 5- (2-ethoxy-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) -3- (4-methoxybenzyl) -3,6-dihydro It was prepared from -7H- [1,2,3] triazolo [4,5-d] pyrimidin-7-one using a similar method as described in previous examples. LCMS (ESI) = 421.2 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ7.99 (d, J = 8.4 Hz, 1H), 7.70-7.59 (m, 2H), 7.48-7.37 (m, 3H) ), 7.33 (s, 1H), 4.32 (d, J = 7.1Hz, 2H), 1.43 (t, J = 6.8Hz, 3H).

Example 115: (R) -2-amino-3- (3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] ] Pyrimidine-5-yl)-[1,1'-biphenyl] -3-yl) Propionic acid (Compound 275) synthesis

(R) -2-Amino-3- (3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5 -Il)-[1,1'-biphenyl] -3-yl) propanoic acid is (R) -3- (3-bromophenyl) -2-((tert-butoxycarbonyl) amino) propanoic acid, and 5- (2-ethoxy-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) -3- (4-methoxybenzyl) -3,6-dihydro It was prepared from -7H- [1,2,3] triazolo [4,5-d] pyrimidin-7-one using a similar method as described in the previous example. LCMS (ESI) = 421.2 [M + H] ⁺ .

Example 116: 2-((3'-ethoxy-5-hydroxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-) Synthesis of 5-yl)-[1,1'-biphenyl] -3-yl) oxy) propionic acid (Compound 276)

2-((3'-ethoxy-5-Hydroxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)) -[1,1'-biphenyl] -3-yl) oxy) propanoate was prepared from lasemimethyl 2- (3-bromo-5-hydroxyphenoxy) propanoate using the procedure of Example 96A. LCMS (ESI) = 438.1 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ7.95 (d, J = 8.2 Hz, 1H), 7.28 (dd, J = 4.5, 2.7 Hz, 2H), 6.69 (d) , J = 7.2Hz, 2H), 6.33 (s, 1H), 4.76 (s, 1H), 4.29 (q, J = 6.9Hz, 2H), 1.49 (d, J) = 6.7Hz, 3H), 1.42 (t, J = 6.9Hz, 3H).

Example 117: rac-trans-2- (3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5 -Il)-[1,1'-biphenyl] -3-yl) Synthesis of cyclopropane-1-carboxylic acid (Compound 277)

Step 1: Add H ₂ SO ₄ (0.50 mL) to a stirred solution of (E) -3- (3-bromophenyl) acrylic acid (2.00 g, 8.81 mmol, 1.00 eq) in EtOH (20 mL). , 9.38 mmol, 1.06 eq) was added dropwise at room temperature. The resulting mixture was stirred at 80 ° C. for 16 hours and then concentrated under reduced pressure. The mixture was diluted with water (50 mL) and extracted with EA (2 x 20 mL). The combined organic layer was washed with brine (30 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain ethyl (E) -3- (3-bromophenyl) acrylate (2.2 g, 98%) as a white solid. ^{1 1} H NMR (300 MHz, CDCl ₃ ) δ7.69 (t, J = 1.8 Hz, 1H), 7.62 (d, J = 16.0 Hz, 1H), 7.52 (ddd, J = 7.9) , 2.0, 1.1Hz, 1H), 7.46 (dt, J = 7.8, 1.5Hz, 1H), 7.28 (t, J = 7.8Hz, 1H), 6.45 ( d, J = 16.0Hz, 1H), 4.47-4.23 (m, 2H), 1.36 (t, J = 7.2Hz, 3H).

Step 2: In a stirred solution of trimethyl sulfoxide (1.12 g, 5.09 mmol, 1.30 eq) in DMSO (10 mL) at room temperature under N ₂ atmosphere, NaH (0.20 g, 5. 10 mmol, 1.3 eq, 60%) were added in several portions. The resulting mixture was stirred for 1 hour. Ethyl (E) -3- (3-bromophenyl) acrylate (1.00 g, 3.920 mmol, 1.00 eq) was added to the above mixture at room temperature. The resulting mixture was stirred at 50 ° C. for 16 hours and then quenched by the addition of room temperature ammonium chloride solution (30 mL). The resulting mixture was extracted with EA (2 x 30 mL). The combined organic layer was washed with brine (30 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give rac-ethyltrans-2- (3-bromophenyl) cyclopropane-1-carboxylate (600 mg, 57%) as a colorless oil. ^{1 1} H NMR (300 MHz, CDCl ₃ ) δ7.35 (ddd, J = 7.9, 2.0, 1.1 Hz, 1H), 7.26 (t, J = 1.9 Hz, 1H), 7.17 (T, J = 7.8Hz, 1H), 7.06 (dt, J = 7.8, 1.5Hz, 1H), 4.20 (q, J = 7.2Hz, 2H), 2.50 ( ddd, J = 9.2,6.5,4.2Hz, 1H), 1.92 (ddd, J = 8.5,5.4,4.2Hz, 1H), 1.63 (ddd, J = 9.2, 5.4, 4.7 Hz, 1H), 1.35-1.25 (m, 4H).

Step 3: rac-ethyltrans-2- (3-bromophenyl) cyclopropane-1-carboxylate (300 mg, 1.12 mmol, 1.00 eq) and bis (pinacolat) diboron (300 mg, 1.12 mmol, 1.00 eq) in dioxane (3.0 mL). In a solution of 340 mg, 1.34 mmol, 1.20 eq), KOAc (219 mg, 2.23 mmol, 2.00 eq) and Pd (dppf) Cl ₂ CH ₂ Cl ₂ (45.5 mg, 0.056 mmol, 0. 05 equivalent) was added. After stirring at 100 ° C. for 2 hours in a nitrogen atmosphere, the resulting mixture was cooled to room temperature. By purifying the mixture by silica gel column chromatography, rac-ethyltrans-2- (3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) as a pale yellow oil) Phenyl) cyclopropane-1-carboxylate (250 mg, 71%) was obtained.

Rac-trans-2- (3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)- [1,1'-Biphenyl] -3-yl) cyclopropane-1-carboxylic acid was prepared using the procedures of Examples 1 and 9. LCMS (ESI) = 418.2 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ11.64 (s, 13H), 8.36 (d, J = 8.4 Hz, 1H), 7.77-7.65 (m, 3H), 7. 64 (s, 1H), 7.58 (t, J = 7.7Hz, 1H), 7.37 (d, J = 7.7Hz, 1H), 4.75 (q, J = 6.9Hz, 2H) ), 2.99 (t, J = 10.2Hz, 1H), 2.19 (dt, J = 8.6, 4.5Hz, 1H), 2.01 (dt, J = 9.7, 5. 1Hz, 1H), 1.79 (t, J = 7.0Hz, 4H).

Example 118: rac-trans-2- (3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5 -Il)-[1,1'-biphenyl] -3-yl) cyclopropane-1-carboxylic acid (Compound 278, Peak 1 and Compound 279, Peak 2) separation of enantiomers

Rac-trans-2- (3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)- [1,1'-Biphenyl] -3-yl) Cyclopropane-1-carboxylic acid (50 mg), chiral preparative HPLC (CHIRALPAK IA-3 column, 20 ^* 250 mm, 5 um, 9 mL / min. Phase A: DCM , Phase B: ethanol (0.1% TFA); 0% phase B up to 30% in 25 minutes) by separation into individual enantiomers to 9 mg trans-2- (3'-ethoxy-4'-(3'-ethoxy-4'-(. 7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)-[1,1'-biphenyl] -3-yl) cyclopropane- 1-Carboxylic Acid, Peak 1, and 10 mg Trans-2- (3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] Triazolo [4,5] -D] Pyrimidine-5-yl)-[1,1'-biphenyl] -3-yl) cyclopropane-1-carboxylic acid, peak 2 was obtained.

Data for compound 278 (peak 1): LCMS (ESI) = 418.2 [M + H] ⁺ . Analytical Chiral HPLC: CHIRALPAK IA-3, 4.6 ^* 50 mm, 3 μm, 1.0 mL / min; A: DCM; B: EtOH w / 0.1% TFA; 80% B: t _R = 1.16 Minutes (99.3% ee). ^* The absolute stereochemistry of a single isolated enantiomer is not determined.

Data for compound 279 (peak 2): LCMS (ESI = 418.2 [M + H] ⁺ . Analytical chiral HPLC: CHIRALPAK IA-3, 4.6 ^* 50 mm, 3 μm, 1.0 mL / min; A: DCM; B : EtOH w / 0.1% TFA; 80% B: t _R = 2.03 minutes (99.7% ee). ^* Absolute steric chemistry of a single isolated enantiomer is not determined.

Example 119: 2-((3'-ethoxy-4-hydroxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-) 5-Il)-[1,1'-biphenyl] -3-yl) Oxy) Propionic acid (Compound 280) synthesis

Step 1: 5-bromo-2-hydroxybenzaldehyde (3.00 g, 14.9 mmol, 1.00 eq) in DMF ( _{30 mL), K2 CO 3 (} 6188 mg, 44.8 mmol, 3.00 eq), and. 4-Methoxybenzyl chloride (2804 mg, 17.9 mmol, 1.20 eq) was placed in a 100 mL round bottom flask. The resulting solution was stirred at 60 ° C. for 4 hours and then quenched by the addition of 10 mL of water at room temperature. The resulting solution was extracted with 3 x 10 mL ethyl acetate, combined with organic layers, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography to obtain 5-bromo-2-((4-methoxybenzyl) oxy) benzaldehyde (4.0 g, 83%) as a white solid. ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ10.28 (s, 1H), 8.01-7.62 (m, 2H), 7.44 (d, J = 8.7Hz, 2H), 7. 33 (d, J = 8.9Hz, 1H), 6.96 (d, J = 8.6Hz, 2H), 5.21 (s, 2H), 3.76 (s, 3H).

Step 2: 5-bromo-2-((4-Methoxybenzyl) oxy) benzaldehyde (1.00 g, 3.11 mmol, 1.00 eq) in DCM (10 mL) is placed in a 50 mL round bottom flask and m-. CPBA (1075 mg, 6.23 mmol, 2.00 eq) was added. The resulting solution was stirred at room temperature for 14 hours. The resulting mixture was concentrated. The residue was purified by silica gel column chromatography to give 5-bromo-2-((4-methoxybenzyl) oxy) phenylformate (900 mg, 86%) as a pale yellow oil. ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ8.51 (s, 1H), 7.57-7.41 (m, 2H), 7.33 (d, J = 8.6 Hz, 2H), 7. 23 (d, J = 8.6Hz, 1H), 7.06-6.85 (m, 2H), 5.07 (s, 2H), 3.76 (s, 3H).

Step 3: In a 50 mL round bottom flask, 5-bromo-2-((4-methoxybenzyl) oxy) phenylformate (900 mg, 2.67 mmol, 1.00 eq), MeOH (5.0 mL), H ₂ A solution of K ₂ CO ₃ (553 mg, 4.00 mmol, 1.50 eq) in O (5 mL) was added. The resulting solution was stirred at room temperature for 4 hours. The pH value of the solution was adjusted to 6 with 1 M HCl. The solids were collected by filtration to give 5-bromo-2-((4-methoxybenzyl) oxy) phenol (750 mg, 91%) as a light brown solid. ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ7.37 (d, J = 8.6 Hz, 1H), 7.01-6.84 (m, 2H), 6.78 (dd, J = 8.5) , 2.4Hz, 1H), 4.99 (s, 1H), 3.75 (s, 3H).

2-((3'-ethoxy-4-hydroxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)) -[1,1'-biphenyl] -3-yl) oxy) propanoic acid is 5- (4-bromo-2-ethoxyphenyl) using a similar method as described in the previous examples. It was prepared from -3,6-dihydro-7H- [1,2,3] triazolo [4,5-d] pyrimidin-7-one. LCMS (ESI) = 438.1 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ7.91 (d, J = 8.1 Hz, 1H), 3.33-7.31 (m, 4H), 6.81 (d, J = 8.1 Hz) , 1H), 4.35-4.20 (m, 3H), 1.50-1.40 (m, 6H).

Example 120: 2-((3'-ethoxy-4-hydroxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-) Synthesis of 5-yl)-[1,1'-biphenyl] -3-yl) oxy) acetic acid (Compound 281)

2-((3'-ethoxy-4-hydroxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)) -[1,1'-biphenyl] -3-yl) oxy) acetic acid was prepared using the procedure of Example 119. LCMS (ESI) = 424.1 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ7.95 (d, J = 8.4 Hz, 1H), 7.34-7.31 (m, 4H), 6.81 (brs, 1H), 4. 32 (q, J = 6.9Hz, 2H), 4.21 (s, 2H), 1.43 (t, J = 6.9Hz, 3H).

Example 121: (S) -3- (3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5) -Il)-[1,1'-biphenyl] -3-yl) -2-hydroxypropanoic acid (Compound 282) synthesis

Step 1: (S) -3- (3-bromophenyl) -2-((tert-butoxycarbonyl) amino) propanoic acid (1.00 g, 2) in HCl (gas) in 1,4-dioxane (15 mL) The solution (.90 mmol, 1.00 eq) was stirred at room temperature for 16 hours. The resulting mixture was diluted with ether (15 mL). The precipitated solid was collected by filtration and washed with ether (3x5 mL). The resulting solid was dried under a heating lamp to give (S) -2-amino-3- (3-bromophenyl) propanoate acid salt (750 mg) as a white solid. LCMS (ESI) = 244.0, 246.0 [M + H] ⁺ .

Step 2: (S) -2-amino-3- (3-bromophenyl) propanoate acid salt (700 mg, 2.50 mmol, 1.00) in H ₂ SO ₄ (1 M in H ₂ O) (10 mL). NaNO ₂ (861 mg, 12.5 mmol, 5.00 equivalent) in H ₂ O (2.0 mL) was added dropwise to the stirred solution of (equivalent) at 0 ° C. under N ₂ atmosphere. The resulting mixture was stirred at room temperature for 16 hours. The resulting mixture was purified by reverse phase flash chromatography under the following conditions to give (S) -3- (3-bromophenyl) -2-hydroxypropionic acid (170 mg, 28%) as an off-white solid. Got LCMS (ESI) = 242.9, 245.0 [MH] ^- .

(S) -3- (3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)- [1,1'-biphenyl] -3-yl) -2-hydroxypropanoic acid is 5- (2-ethoxy-4- (4,4,5,5-tetra) using the procedure of Example 42. Methyl-1,3,2-dioxaborolan-2-yl) phenyl) -3- (4-methoxybenzyl) -3,6-dihydro-7H- [1,2,3] triazolo [4,5-d] pyrimidine Prepared from -7-one. LCMS (ESI) = 422.1 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ7.98 (d, J = 7.7 Hz, 1H), 7.67-7.56 (m, 2H), 7.39 (d, J = 4.3 Hz) , 3H), 7.29 (d, J = 7.4Hz, 1H), 4.31 (q, J = 7.0Hz, 2H), 4.12 (s, 1H), 3.14-3.07 (M, 1H), 2.91-2.82 (m, 1H), 1.43 (t, J = 6.9Hz, 3H).

Example 122: (S) -3- (3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5) -Il)-[1,1'-biphenyl] -3-yl) -2-Methoxypropaneic acid (Compound 283) synthesis

NaH (33.3 mg, 0) in a stirred solution of (S) -2-hydroxy-3- (3-methylphenyl) propanoic acid (100 mg, 0.555 mmol, 1.00 eq) in DMF (1.0 mL). .832 mmol, 1.50 eq, 60%) was added in several portions at room temperature. The resulting mixture was stirred for 20 minutes, after which MeI (158 mg, 1.11 mmol, 2.00 equal amount) was added. The resulting mixture was stirred at room temperature for an additional 5 hours. The mixture was purified by reverse phase flash chromatography to give (S) -2-methoxy-3- (3-methylphenyl) propionic acid (70 mg, 65%) as a yellow solid. ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ12.78 (s, 1H), 7.47-7.35 (m, 2H), 7.31-7.19 (m, 2H), 3.97 ( dd, J = 7.8, 4.9Hz, 1H), 2.99 (dd, J = 14.1, 4.7Hz, 1H), 2.88 (dd, J = 14.1,7.8Hz, 1H).

(S) -3- (3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)- [1,1'-biphenyl] -3-yl) -2-methoxypropanoic acid is 5- (2-ethoxy-4- (4,4,5,5-tetra) using the procedure of Example 42. Methyl-1,3,2-dioxaborolan-2-yl) phenyl) -3- (4-methoxybenzyl) -3,6-dihydro-7H- [1,2,3] triazolo [4,5-d] pyrimidine Prepared from -7-one. LCMS (ESI) = 436.1 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ8.04-7.95 (m, 1H), 7.61 (d, J = 8.0 Hz, 2H), 7.46-7.33 (m, 3H) ), 7.28 (d, J = 7.6Hz, 1H), 4.32 (q, J = 6.9Hz, 2H), 4.00 (s, 1H), 3.25 (s, 3H), 3.10 (dd, J = 14.0, 4.6Hz, 1H), 2.97 (dd, J = 14.2,8.1Hz, 1H), 1.43 (t, J = 6.9Hz, 3H).

Example 123: (R) -3- (3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5) -Il)-[1,1'-biphenyl] -3-yl) -2-hydroxypropanoic acid (Compound 284) synthesis

(R) -3- (3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)- [1,1'-biphenyl] -3-yl) -2-hydroxypropanoic acid was added to (R) -3- (3-bromophenyl) -2-((tert-) using the procedure of Example 121. It was prepared from butoxycarbonyl) amino) propionic acid.

Example 124: (R) -3- (3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5) -Il)-[1,1'-biphenyl] -3-yl) -2-Methoxypropaneic acid (Compound 285) synthesis

(R) -3- (3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)- [1,1'-biphenyl] -3-yl) -2-methoxypropanoic acid is derived from (R) -2-hydroxy-3- (3-methylphenyl) propanoic acid using the procedure of Example 122. Prepared. LCMS (ESI) = 436.1 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ8.01 (d, J = 8.1 Hz, 1H), 7.61 (d, J = 9.2 Hz, 2H), 7.46-7.34 (m) , 3H), 7.28 (d, J = 7.5Hz, 1H), 4.32 (q, J = 6.9Hz, 2H), 3.97 (s, 1H), 3.25 (s, 3H) ), 3.11 (d, J = 14.1Hz, 1H), 3.04-2.91 (m, 1H), 1.43 (t, J = 6.9Hz, 3H).

Example 125: 2'-Nitro-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)-[1, Synthesis of 1'-biphenyl] -4-carboxylic acid (Compound 286)

2'-Nitro-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)-[1,1'-biphenyl ] -4-Carboxylic acid was prepared from 4-bromo-3-nitrobenzaldehyde using the procedures of Examples 6 and 9. LCMS (ESI) = 377.0 [MH] ^- . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ8.77 (s, 1H), 8.53 (d, J = 8.1 Hz, 1H), 8.02 (d, J = 7.8 Hz, 2H), 7.71 (d, J = 7.8Hz, 1H), 7.48 (d, J = 7.5Hz, 2H), 1.24 (s, 1H).

Example 126: 2'-amino-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)-[1, Synthesis of 1'-biphenyl] -4-carboxylic acid (Compound 287)

Methyl 4'-(3- (4-methoxybenzyl) -7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-] in MeOH (8 mL) and EA (8 mL) d] Pd / C (80.0 mg) in a solution of pyrimidine-5-yl) -2'-nitro- [1,1'-biphenyl] -4-carboxylate (800 mg, 1.56 mmol, 1.00 equivalent). ) Was added. H ₂ (g) was introduced and the solution was stirred under H ₂ atmosphere at room temperature for 6 hours. By filtering the solid and concentrating the resulting mixture under reduced pressure, the brown solid is methyl 2'-amino-4'-(3- (4-methoxybenzyl) -7-oxo-6,7. -Dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)-[1,1'-biphenyl] -4-carboxylate (500 mg, 66%) was obtained. LCMS (ESI) = 483.2 [M + H] ⁺ .

2'-Amino-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)-[1,1'-biphenyl ] -4-Carboxylic acid was prepared using the procedures of Examples 6 and 9. LCMS (ESI) = 349.0 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ8.03 (d, J = 8.4 Hz, 2H), 7.62-7.56 (m, 3H), 7.37 (dd, J = 8.1) , 1.8Hz, 1H), 7.14 (d, J = 8.1Hz, 1H), 5.11 (s, 2H).

Example 127: 2'-(dimethylamino) -4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)- Synthesis of [1,1'-biphenyl] -4-carboxylic acid (Compound 288)

Methyl 2'-amino-4'-(3- (4-methoxybenzyl) -7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,2,3] in HOAc (0.30 mL) 5-d] Pyrimidine-5-yl)-[1,1'-biphenyl] -4-carboxylate (80 mg, 0.166 mmol, 1.00 eq) and HCHO (0.30 ml, 37%) in an 8 mL vial I put it in. The resulting solution was stirred at room temperature for 10 minutes. NaBH (OAc) ₃ (13.3 mg, 1.66 mmol, 10.0 equal amount) was added. The resulting solution was reacted at room temperature for an additional 30 minutes with stirring. The reaction was then quenched by the addition of 1 mL of water. The resulting solution was extracted with 3 x 5 mL dichloromethane, and the combined organic layer was dried over anhydrous sodium sulfate and concentrated to give methyl 2'-(dimethylamino) -4'-(dimethylamino) -4'-(. 3- (4-Methoxybenzyl) -7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)-[1,1'-biphenyl ] -4-carboxylate (50 mg) was obtained. LCMS (ESI) = 511.3 [M + H] ⁺ .

2'-(dimethylamino) -4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)-[1,1 '-Biphenyl] -4-carboxylic acid was prepared using the procedures of Examples 6 and 9. LCMS (ESI) = 377.1 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ8.02 (d, J = 8.4 Hz, 2H), 7.80-7.78 (m, 2H), 7.73 (d, J = 8.4 Hz) , 2H), 7.34 (d, J = 8.4Hz, 1H), 2.58 (s, 6H).

Example 128: 2'-(cyclohexylamino) -4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)- Synthesis of [1,1'-biphenyl] -4-carboxylic acid (Compound 289)

2'-(cyclohexylamino) -4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)-[1,1 '-Biphenyl] -4-carboxylic acid was prepared using the procedure of Example 127. LCMS (ESI) = 431.2 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ8.05 (d, J = 8.4 Hz, 1H), 7.56 (d, J = 8.1 Hz, 1H), 7.45 (dd, J = 3) .3, 1.5Hz, 1H), 7.13 (d, J = 8.4Hz, 1H), 3.52-3.34 (m, 2H), 1.95-1.91 (m, 2H) , 1.65-1.61 (m, 3H), 1.43-1.32 (m, 2H), 1.24-1.05 (m, 4H).

Example 129: 2'-(benzylamino) -4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)- Synthesis of [1,1'-biphenyl] -4-carboxylic acid (Compound 290)

2'-(Benzylamino) -4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)-[1,1 '-Biphenyl] -4-carboxylic acid was prepared using the procedure of Example 127. 8.06 (d, J = 8.1Hz, 2H), 7.62 (d, J = 8.1Hz, 2H), 7.43 (d, J = 8.1Hz, 1H), 7.38-7 .29 (m, 5H), 7.17 (dd, J = 19.8, 7.2Hz, 1H), 5.51 (s, 1H), 4.47 (d, J = 5.4Hz, 1H) ..

Example 130: 4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl) -2'-(propylamino- [ Synthesis of 1,1'-biphenyl] -4-carboxylic acid (Compound 291)

Methyl 2'-amino-4'-(3- (4-methoxybenzyl) -7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,3] in DCE (1.0 mL) 5-d] Pyrimidine-5-yl)-[1,1'-biphenyl] -4-carboxylate (80.0 mg, 0.166 mmol, 1.00 eq), and propionaldehyde (9.63 mg, 0.166 mmol). , 1.00 equivalent) was added with Ti addition (OiPr) ₄ (75.6 mg, 0.332 mmol, 2.00 equivalent). The resulting solution was stirred at room temperature for 10 minutes. NaBH (OAc) ₃ (87.8 mg, 0.415 mmol, 2.50 eq) was added and the mixture was stirred for 2 hours at room temperature. The reaction was quenched with 5 mL of water and the solids were removed by filtration. The filtrate was extracted with 3 x 5 mL dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure. As a result, as a yellow solid, methyl 4'-(3- (4-methoxybenzyl) -7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin- 5-Il) -2'-(propylamino)-[1,1'-biphenyl] -4-carboxylate (90 mg) was obtained. LCMS (ESI) = 525.4 [M + H] ⁺ .

4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl) -2'-(propylamino)-[1,1 '-Biphenyl] -4-carboxylic acid was prepared using the procedures of Examples 6 and 9. LCMS (ESI) = 391.1 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ8.06-8.03 (m, 2H), 7.56 (d, J = 8.1 Hz, 2H), 7.47-743 (m, 2H) ), 7.12 (d, J = 8.1Hz, 1H), 4.72 (s, 1H), 3.20-3.15 (m, 2H), 1.58 (q, J = 7.2Hz) , 2H), 0.91 (t, J = 7.2Hz, 3H).

Example 131: 2'-(ethylamino) -4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)- Synthesis of [1,1'-biphenyl] -4-carboxylic acid (Compound 292)

2'-(ethylamino) -4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)-[1,1 '-Biphenyl] -4-carboxylic acid was prepared using the procedure of Example 130. LCMS (ESI) = 377.1 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ8.01 (d, J = 9 Hz, 2H), 7.51-7.43 (m, 4H), 7.10 (d, J = 7.8 Hz, 1H) ), 4.70-4.60 (m, 1H), 3.23 (d, J = 6.9Hz, 2H), 1.15 (t, J = 7.2Hz, 3H).

Example 132: (S) -2-acetamide-3- (3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] ] Pyrimidine-5-yl)-[1,1'-biphenyl] -3-yl) Propionic acid (Compound 293) synthesis

(S) -2-Amino-3- (3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5] in DCM (1 mL) -D] Pyrimidine-5-yl)-[1,1'-biphenyl] -3-yl) propionic acid (15.0 mg, 0.036 mmol, 1.00 eq) was placed in an 8 mL vial. Et 3N (10.8 mg _, 0.107 mmol, 3.00 eq) was added, followed by acetyl chloride (2.8 mg, 0.036 mmol, 1.00 eq) at 0 ° C. The resulting solution was stirred at room temperature for 3 hours. By concentrating the resulting mixture and purifying the crude product by preparative HPLC, (S) -2-acetamide-3- (3'-ethoxy-4'-(7-oxo-6,7-) Dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)-[1,1'-biphenyl] -3-yl) propionic acid (3.5 mg, 21%) Obtained. LCMS (ESI) = 463.1 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ11.46 (brs, 1H), 8.21 (d, J = 7.5 Hz, 1H), 7.96 (d, J = 8.1 Hz, 1H), 7.62 (d, J = 9.0Hz, 2H), 7.44-7.39 (m, 3H), 7.28 (d, J = 7.5Hz, 1H), 4.48-4.46 (M, 1H), 4.35-4.28 (m, 2H), 3.15-2.90 (m, 2H), 1.80 (s, 3H), 1.42 (t, J = 6) .6Hz, 3H).

Example 133: Ethyl 2- (3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)) -Synthesis of [1,1'-biphenyl] -3-yl) acetate (Compound 294)

Ethyl 2- (3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)-[1, 1'-biphenyl] -3-yl) acetic acid was prepared from 2- (3-bromophenyl) acetic acid using the procedure of Example 42. LCMS (ESI) = 420.2 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ7.94 (d, J = 8.0 Hz, 1H), 7.64 (d, J = 8.4 Hz, 2H), 7.45 (t, J = 7) .6Hz, 1H), 7.41-7.33 (m, 2H), 7.29 (d, J = 7.6Hz, 1H), 4.27 (q, J = 6.9Hz, 2H), 4 .07 (q, J = 7.1Hz, 2H), 3.73 (s, 2H), 1.38 (t, J = 6.9Hz, 3H), 1.17 (t, J = 7.1Hz, 3H).

Example 134: 2- (3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)- Synthesis of [1,1'-biphenyl] -3-yl) acetic acid (Compound 295)

2- (3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)-[1,1 '-Biphenyl] -3-yl) acetic acid was prepared using the procedures of Examples 42 and 9. LCMS (ESI) = 392.1 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ8.00 (d, J = 8.5 Hz, 1H), 7.71-7.61 (m, 2H), 7.44 (t, J = 7.6 Hz) , 1H), 7.42-7.35 (m, 2H), 7.32 (d, J = 7.7Hz, 1H), 4.32 (q, J = 6.9Hz, 2H), 1.43 (T, J = 6.9Hz, 3H).

Example 135: Ethyl 2- (3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)) -Synthesis of [1,1'-biphenyl] -3-yl) propanoate (Compound 296)

Ethyl 2- (3-bromophenyl) acetate (500 mg, 2.06 mmol, 1.00 eq), THF (10 ml), MeI (1.46 mg, 10.3 mmol, 5.00 eq), and Cs ₂ CO ₃ ( 3.35 g, 10.3 mmol, 5.0 eq) was added to a 40 mL vial. The mixture was stirred at 60 ° C. for 3 hours. The resulting mixture was diluted with water (40 mL) and extracted with Et ₂ O (3 x 40 mL). The combined organic layer was washed with brine (2 x 40 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give ethyl 2- (3-bromophenyl) propanoate as a yellow oil. (400 mg, 68%) was obtained. ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ7.53-7.40 (m, 1H), 7.38 (s, 1H), 7.36-7.24 (m, 2H), 4.06 ( qq, J = 7.2,3.8Hz, 2H), 3.82 (q, J = 7.1Hz, 1H), 1.38 (d, J = 7.2Hz, 3H), 1.13 (t) , J = 7.1Hz, 3H).

Ethyl 2- (3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)-[1, 1'-biphenyl] -3-yl) propanoate was prepared using the procedure of Example 42.

Example 136: 2- (3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)- Synthesis of [1,1'-biphenyl] -3-yl) propanoic acid (Compound 297)

2- (3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)-[1,1 '-Biphenyl] -3-yl) propanoate was prepared from ethyl 2- (3-bromophenyl) propanoate using the procedures of Examples 42 and 9. LCMS (ESI) = 406.2 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ11.42 (s, 1H), 7.97 (d, J = 8.5 Hz, 1H), 7.70-7.61 (m, 2H), 7. 46 (t, J = 7.6Hz, 1H), 7.41-7.31 (m, 3H), 4.32 (q, J = 6.9Hz, 2H), 3.79 (q, J = 7) .1Hz, 1H), 1.49-1.37 (m, 6H).

Example 137: 2- (3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)- Synthesis of [1,1'-biphenyl] -3-yl) -2-methylpropanoic acid (Compound 298)

2- (3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)-[1,1 '-Biphenyl] -3-yl) -2-methylpropanoate was prepared from methyl 2- (3-bromophenyl) -2-methylpropanoate using the procedures of Examples 42 and 9. LCMS (ESI) = 420.2 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ7.98 (d, J = 8.4 Hz, 1H), 7.69-7.59 (m, 2H), 7.47 (t, J = 7.5 Hz) , 1H), 7.45-7.32 (m, 3H), 4.31 (q, J = 6.9Hz, 2H), 1.56 (s, 6H), 1.42 (t, J = 6) .9Hz, 3H).

Example 138: (E) -3- (3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidine-5) -Il) -4- (2- (pyrrolidin-1-yl) ethoxy)-[1,1'-biphenyl] -3-yl) -2-methylacrylic acid (Compound 299)

Step 1: 5-bromo-2-hydroxybenzaldehyde (2.00 g, 9.95 mmol, 1.00 eq), 1- (2-chloroethyl) pyrrolidine hydrochloride (1.33 g, 9.95 mmol, 1.0 eq) , K ₂ CO ₃ (2.75 g, 19.9 mmol, 2.00 eq), and DMF (20 mL) were added to a 40 mL vial at room temperature. The resulting mixture was stirred at 80 ° C. for 2 hours. The mixture was cooled to room temperature and then the resulting mixture was diluted with water (40 mL). The mixture was extracted with Et ₂ O (3 x 30 mL). The combined organic layer was washed, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 5-bromo-2- (2- (pyrrolidin-1-yl) ethoxy) benzaldehyde (700 mg, 22%) as a yellow oil. ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ10.41 (s, 1H), 7.91 (d, J = 2.6 Hz, 1H), 7.61 (dd, J = 8.8, 2.7 Hz) , 1H), 6.90 (d, J = 8.9Hz, 1H), 4.22 (t, J = 5.8Hz, 2H), 3.01-2.93 (m, 2H), 2.91 (S, 1H), 2.73-2.55 (m, J = 3.4, 2.2Hz, 4H), 1.90-1.72 (m, J = 3.8, 3.2Hz, 4H) ).

Step 2: 5-bromo-2- (2- (pyrrolidin-1-yl) ethoxy) benzaldehyde (700 mg, 2.35 mmol, 1.00 eq), methylmalonic acid (333 mg, 2.82 mmol, 1.2 eq) , Piperidine (399 mg, 4.69 mmol, 2.0 eq), and pyridine (15 mL) were added to a 40 mL vial at room temperature. The resulting mixture was stirred at 80 ° C. for 10 hours. By purifying the residue by reverse phase flash chromatography, (E) -3- (5-bromo-2- (2- (pyrrolidin-1-yl) ethoxy) phenyl) -2-methylacrylic acid as a yellow solid is obtained. (400 mg, 46%) was obtained. ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ7.63-7.56 (m, 1H), 7.53-7.35 (m, 2H), 7.05 (d, J = 8.8Hz, 1H) ), 4.12 (t, J = 5.8Hz, 2H), 2.82 (t, J = 5.8Hz, 2H), 2.55 (t, J = 5.8Hz, 4H), 1.92 (D, J = 1.5Hz, 3H), 1.67 (h, J = 3.1Hz, 4H).

(E) -3- (3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)- 4- (2- (Pyrrolidine-1-yl) ethoxy)-[1,1'-biphenyl] -3-yl) -2-methylacrylic acid was prepared using the procedure of Example 42. LCMS (ESI) = 531.4 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ11.53 (s, 1H), 7.94 (d, J = 8.4 Hz, 1H), 7.80-7.67 (m, 3H), 7. 36 (d, J = 6.8Hz, 2H), 7.21 (d, J = 8.7Hz, 1H), 4.34 (d, J = 6.8Hz, 1H), 4.26 (dd, J) = 13.7, 8.0Hz, 3H), 2.99 (t, J = 5.7Hz, 2H), 2.72 (d, J = 6.0Hz, 4H), 2.01 (d, J = 1.5Hz, 3H), 1.74 (p, J = 3.0Hz, 4H), 1.41 (t, J = 6.9Hz, 3H)

Example 139: 3- (3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)- Synthesis of 4- (2- (pyrrolidin-1-yl) ethoxy)-[1,1'-biphenyl] -3-yl) -2-methylpropanoic acid (Compound 300)

(E) -3- (3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)- 4- (2- (Pyrrolidine-1-yl) ethoxy)-[1,1'-biphenyl] -3-yl) -2-methylacrylic acid (200 mg, 0.377 mmol, 1.00 equivalent), Pd (OH) ) ₂ / C (80.0 mg, 0.752 mmol, 1.99 eq), and MeOH (20 mL) were added to a 100 mL round bottom flask at room temperature. The gas was replaced with H ₂ three times. The resulting mixture was stirred at H2 at 50 ° C. for ₂ hours. The resulting mixture was filtered and the filter cake was washed with MeOH (3 x 10 mL). The filtrate was concentrated under reduced pressure. The crude product is purified by preparative HPLC to give 3- (3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo] as a white solid. 4,5-d] Pyrimidine-5-yl) -4- (2- (pyrrolidin-1-yl) ethoxy)-[1,1'-biphenyl] -3-yl) -2-methylpropanoic acid (24. 8 mg, 12.0%) was obtained. LCMS (ESI) = 533.3 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ11.32 (s, 1H), 7.97 (d, J = 8.5 Hz, 1H), 7.65-7.51 (m, 2H), 7. 34 (dt, J = 4.3, 2.1Hz, 2H), 7.05 (d, J = 8.6Hz, 1H), 4.32 (q, J = 6.9Hz, 2H), 4.16 (T, J = 5.4Hz, 2H), 2.96 (dt, J = 14.0, 6.1Hz, 3H), 2.72 (h, J = 6.9Hz, 6H), 1.77 ( s, 4H), 1.82-1.71 (m, 1H), 1.43 (t, J = 6.9Hz, 3H), 1.05 (d, J = 6.6Hz, 3H).

Example 140: (E) -3- (3'-ethoxy-4-isopropoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-] d] Synthesis of pyrimidine-5-yl)-[1,1'-biphenyl] -3-yl) -2-methylacrylic acid (Compound 301)

(E) -3- (3'-ethoxy-4-isopropoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-) 5-Il)-[1,1'-biphenyl] -3-yl) -2-methylacrylic acid was prepared from iodopropane using the procedure of Example 138. LCMS (ESI) = 476.1 [M + H] ⁺ .

Examples 141: 3- (3'-ethoxy-4-isopropoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-) 5-Il)-[1,1'-biphenyl] -3-yl) -2-Methylpropionic acid (Compound 302) synthesis

3- (3'-ethoxy-4-isopropoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl) -[1,1'-biphenyl] -3-yl) -2-methylpropionic acid was prepared using the procedure of Example 139. LCMS (ESI) = 478.2 [M + H] ⁺ .

Example 142: 3- (3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)- [1,1'-biphenyl] -3-yl) -3-methylbutanoic acid (Compound 303) and 3- (3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H-]-[1, 2,3] Triazolo [4,5-d] pyrimidin-5-yl)-[1,1'-biphenyl] -4-yl) -3-methylbutanoic acid (Compound 304) synthesis

Add 3-methylbut-2-enoic acid (200 mg, 2.00 mmol, 1.00 eq), bromobenzene (627 mg, 4.00 mmol, 2.0 eq), and DCM (2.0 mL) into an 8 mL vial. did. AlCl ₃ (799 mg, 5.99 mmol, 3.0 eq) was added to the mixture at 0 ° C. over 2 minutes in several batches. The resulting mixture was stirred at 0 ° C. for an additional hour. The reaction was quenched by the addition of water (40 mL) and HCl concentrated at 0 ° C. (4 mL). The mixture was extracted with DCM (3 x 40 mL). The combined organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. Purification of the residue by reverse phase flash chromatography gives a mixture of 3- (3-bromophenyl) -3-methylbutanoic acid and 3- (4-bromophenyl) -3-methylbutanoic acid (280 mg) as white oil. rice field.

3- (3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)-[1,1 '-Biphenyl] -3-yl) -3-methylbutanoic acid, and 3- (3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4] , 5-d] Pyrimidine-5-yl)-[1,1'-biphenyl] -4-yl) -3-methylbutanoic acid, continued mixing of the compounds, and two final compounds after the final step. By purification, it was prepared using the procedure of Example 42.

3- (3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)-[1,1 '-Biphenyl] -3-yl) -3-methylbutanoic acid data: LCMS (ESI) = 434.3 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ8.03 (d, J = 7.9 Hz, 1H), 7.72 (s, 1H), 7.56 (d, J = 6.3 Hz, 1H), 7.47-7.34 (m, 4H), 4.33 (q, J = 7.0Hz, 2H), 3.30 (s, 1H), 2.67 (s, 2H), 1.46 ( s, 6H), 1.43 (d, J = 6.9Hz, 2H).

3- (3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)-[1,1 '-Biphenyl] -4-yl) -3-methylbutanoic acid data: LCMS (ESI) = 434.3 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ8.00 (d, J = 8.5 Hz, 1H), 7.70 (d, J = 8.4 Hz, 2H), 7.51 (d, J = 8) .4Hz, 2H), 7.39 (dt, J = 4.3, 2.1Hz, 2H), 4.32 (q, J = 6.9Hz, 2H), 2.64 (s, 2H), 1 .51-1.37 (m, 9H).

Example 143: 5- (4- (3,3-dimethyl-2-oxochloroman-6-yl) -2-ethoxyphenyl) -3,6-dihydro-7H- [1,2,3] triazolo [ 4,5-d] Synthesis of pyrimidine-7-one (Compound 305)

Step 1: 5-bromo-2,3-dihydroinden-1-one (1.00 g, 4.73 mmol, 1.00 eq) and THF (15 mL), Cs ₂ CO ₃ (7.72 g, 23.7 mmol, 5.0 eq), MeI (3.36 g, 23.7 mmol, 5.0 eq) was added to an 8 mL vial at room temperature. The resulting mixture was stirred at 65 ° C. for 12 hours. The mixture was cooled to room temperature. The resulting mixture was filtered and the filter cake was washed with THF (3 x 40 ml). The filtrate was concentrated under reduced pressure to give 5-bromo-2,2-dimethyl-3H-indene-1-one (1.0 g, 77.0%) as a yellow oil. ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ7.62 (dd, J = 6.1, 0.7 Hz, 1H), 7.60 (s, 1H), 7.51 (ddt, J = 8.1) , 1.7, 0.8Hz, 1H), 2.98 (d, J = 1.2Hz, 2H), 1.23 (s, 6H).

Step 2: 5-bromo-2,2-dimethyl-3H-inden-1-one (1.00 g, 4 mmol, 1.00 eq) and mCPBA (1.44 g, 8 mmol, 2.0) in DCM (25 mL). CF ₃ SO ₃ H (1.26 g, 8 mmol, 2.01 eq) was added to the stirred solution (equivalent) in several batches at 0 ° C. The resulting mixture was stirred at room temperature for 12 hours and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 6-bromo-3,3-dimethyl-4H-1-benzopyran-2-one (250 mg, 22.2%) as a yellow solid. ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ7.57-7.41 (m, 2H), 7.03 (d, J = 8.5 Hz, 1H), 2.94 (s, 2H), 1. 18 (s, 6H).

5- (4- (3,3-dimethyl-2-oxochloroman-6-yl) -2-ethoxyphenyl) -3,6-dihydro-7H- [1,2,3] triazolo [4,5- d] Pyrimidine-7-one was prepared using the procedure of Example 42. LCMS (ESI) = 432.1 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ12.23 (s, 1H), 7.88 (dd, J = 7.9, 4.1 Hz, 1H), 7.77-7.68 (m, 2H) ), 7.44 (s, 2H), 7.41 (d, J = 1.6Hz, 0H), 7.24-7.15 (m, 1H), 4.32 (q, J = 6.9Hz) , 2H), 3.04 (s, 2H), 1.40 (t, J = 6.9Hz, 3H), 1.24 (s, 6H).

Example 144: rac-cis-2- (3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5] -Il)-[1,1'-biphenyl] -3-yl) Synthesis of cyclopropane-1-carboxylic acid (Compound 306)

Step 1: Cyclopropane in a stirred solution of 8-aminoquinoline (3.00 g, 20.8 mmol, 1.00 eq) and TEA (3.16 g, 31.2 mmol, 1.50 eq) in DCM (30 mL). Carbonyl chloride (2.39 g, 22.9 mmol, 1.10 eq) was added dropwise at 0 ° C. under _N2 . The mixture was stirred at room temperature for 2 hours and then the reaction was quenched by the addition of water (100 mL). The resulting mixture was extracted with DCM (3x30 mL). The combined organic layer was washed with brine (50 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give N- (quinoline-8-yl) cyclopropanecarboxamide (4.2 g, 95%) as a yellow oil. ^{1 1} H NMR (300 MHz, CDCl ₃ ) δ10.04 (s, 1H), 8.84 (dd, J = 4.2, 1.7 Hz, 1H), 8.77 (dd, J = 7.1, 1) 9.9Hz, 1H), 8.19 (dd, J = 8.3, 1.7Hz, 1H), 7.61-7.43 (m, 3H), 1.84 (tt, J = 7.8, 4.5Hz, 1H), 1.27-1.14 (m, 2H), 0.94 (dt, J = 7.9, 3.4Hz, 2H).

Step 2: N- (quinoline-8-yl) cyclopropanecarboxamide in toluene (10 mL) (1.00 g, 4.71 mmol, 1.00 eq) and 1-bromo-3-iodobenzene (1.33 g, 4). Silver acetate (865 mg, 5.18 mmol, 1.10 eq) and Pd (OAc) ₂ (0.05 g, 0.24 mmol, .71 mmol, 1.00 eq) at room temperature in an _N2 atmosphere. 0.05 equivalent) was added. The resulting mixture was stirred at 110 ° C. for 16 hours. After cooling to room temperature, the mixture was filtered and the filter cake was washed with EA (3 x 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain rac-2- (3-bromophenyl) -N- (quinoline-8-yl) cyclopropane-1-carboxamide (900 mg, 52%) as a yellow oil. .. ^{1 1} H NMR (300 MHz, CDCl ₃ ) δ9.94 (s, 1H), 8.84 (dd, J = 4.3, 1.7 Hz, 1H), 8.67-8.50 (m, 1H), 8.17 (dd, J = 8.3, 1.7Hz, 1H), 7.54 (d, J = 2.0Hz, 1H), 7.54-7.39 (m, 3H), 7.37 -7.23 (m, 2H), 7.16-7.02 (m, 1H), 2.62 (q, J = 8.4Hz, 1H), 2.36 (td, J = 8.5) 5.6Hz, 1H), 1.90 (dt, J = 7.5,5.4Hz, 1H), 1.47 (ddd, J = 8.7, 7.9, 5.1Hz, 1H).

Step 3: rac-cis-2- (3-bromophenyl) -N- (quinoline-8-yl) cyclopropane-1-carboxamide (900 mg, 2.45 mmol, 1.00 eq) in MeCN (10 mL) and DMAP (29.9 mg, 0.245 mmol, 0.10 eq) was added to a stirred solution of di-tert-butyl dicarbonate (1281 mg, 7.35 mmol, 3.00 eq) at room temperature. The resulting mixture was stirred at 60 ° C. for 3 hours. After cooling, the resulting mixture was concentrated under reduced pressure. By purifying the residue by silica gel column chromatography, rac-tert-butyl cis-2- (3-bromophenyl) cyclopropane-1-carbonyl) (quinoline-8-yl) carbamate (1.2 g) was used as a yellow oil. Got LCMS (ESI) = 467.1,469.1 [M + H] ⁺ .

Step 4: rac-tert-butylsis-2- (3-bromophenyl) cyclopropane-1-carbonyl) (quinoline-8-yl) carbamate in EtOH (10 mL) (1.00 g, 2.14 mmol, 1.00 g) Equivalent) and a solution of K ₂ CO ₃ (0.59 g, 4.28 mmol, 2.00 eq) were stirred at 80 ° C. for 16 hours. The mixture was cooled to room temperature. The resulting mixture was filtered and the filter cake was washed with DCM (2 x 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give rac-ethyl cis-2- (3-bromophenyl) cyclopropane-1-carboxylate (500 mg, 87%) as a pale yellow oil. ^{1 1} H NMR (300 MHz, CDCl ₃ ) δ7.44 (d, J = 2.1 Hz, 1H), 7.35 (dt, J = 7.6, 1.8 Hz, 1H), 7.26-7.10 (M, 2H), 3.94 (q, J = 7.1Hz, 2H), 2.56 (q, J = 8.7Hz, 1H), 2.11 (ddd, J = 9.3,7. 9,5.7Hz, 1H), 1.71 (dt, J = 7.4,5.4Hz, 1H), 1.43-1.28 (m, 1H), 1.04 (t, J = 7) .1Hz, 3H).

Rac-cis-2- (3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)- [1,1'-Biphenyl] -3-yl) cyclopropane-1-carboxylic acid was prepared using the procedures of Examples 58 and 9. LCMS (ESI) = 418.2 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ8.01 (d, J = 8.4 Hz, 1H), 7.59 (d, J = 9.1 Hz, 2H), 7.44-7.33 (m) , 3H), 7.30 (d, J = 7.5Hz, 1H), 4.32 (q, J = 6.9Hz, 2H), 2.72-2.60 (m, 1H), 2.18 -2.01 (m, 1H), 1.67-1.55 (m, 1H), 1.49-1.29 (m, 4H).

Example 145: rac-cis-2- (3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5] -Il)-[1,1'-biphenyl] -3-yl) cyclopropane-1-carboxylic acid (Compound 307, Peak 1, and Compound 308, Peak 2) separation of enantiomers

Sis-2- (3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)-[1 , 1'-biphenyl] -3-yl) cyclopropane-1-carboxylic acid, peak 1, and cis-2- (3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H-) [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)-[1,1'-biphenyl] -3-yl) cyclopropane-1-carboxylic acid, peak 2 is Example 118. It was isolated into its individual enantiomers using the procedure of.

Data for compound 307 (peak 1) LCMS (ESI) = 418.1 [M + H] +. Analytical Chiral HPLC: CHIRALPAK ID-3, 4.6 ^* 50 mm, 3 μm, 1.0 mL / min; A: n-hexane: DCM 3/1; B: EtOH (0.5% FA); 15% B : T _R = 1.74 minutes (100% ee). ^* The absolute stereochemistry of a single isolated enantiomer is not determined.

Data for compound 308 (peak 2): LCMS (ESI) = 418.1 [M + H] ⁺ . CHIRALPAK ID-3, 4.6 ^* 50 mm, 3 μm, 1.0 mL / min; A: n-hexane: DCM 3/1; B: EtOH (0.5% FA); 15% B: t _R = 2 .57 minutes (98.9% ee). ^* The absolute stereochemistry of a single isolated enantiomer is not determined.

Examples 146: 3- (3'-ethoxy-4-hydroxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5 -Il)-[1,1'-biphenyl] -3-yl) Propionic acid (Compound 309) synthesis

3- (3'-ethoxy-4-hydroxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)- [1,1'-biphenyl] -3-yl) propionic acid was prepared from 6-bromochroman-2-one using the procedures of Examples 42 and 9. LCMS (ESI) = 422.2 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ12.09 (s, 1H), 9.72 (s, 1H), 7.86 (dd, J = 8.5, 4.1 Hz, 1H), 7. 54 (t, J = 3.3Hz, 1H), 7.47 (dd, J = 7.4,3.5Hz, 1H), 7.38-7.28 (m, 2H), 6.91 (dd) , J = 8.4,4.0Hz, 1H), 4.30 (dq, J = 10.4, 6.3, 4.6Hz, 2H), 2.85 (td, J = 8.5,7) 9.9, 3.9Hz, 2H), 2.57 (dd, J = 7.7, 3.9Hz, 1H), 2.49 (s, 1H), 1.41 (td, J = 6.8, 3.6Hz, 3H).

Example 147: Methyl 3- (3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)) -Synthesis of [1,1'-biphenyl] -3-yl) -2-methylpropanoate (Compound 310)

Methyl 3- (3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)-[1, 1'-biphenyl] -3-yl) -2-methylpropanoate was prepared using the procedure of Example 81. LCMS (ESI) = 434.1 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ12.12 (s, 1H), 7.93-7.84 (m, 1H), 7.67-7.57 (m, 2H), 7.48- 7.36 (m, 3H), 7.24 (d, J = 7.5Hz, 1H), 4.32 (q, J = 6.9Hz, 2H), 3.58 (s, 3H), 3. 01 (dd, J = 12.4, 6.5Hz, 1H), 2.95-2.73 (m, 2H), 1.41 (t, J = 6.9Hz, 3H), 1.11 (d) , J = 6.7Hz, 3H).

Example 148: 3- (3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)- Synthesis of enantiomers of [1,1'-biphenyl] -3-yl) -2-methylpropanoic acid (Compound 311 and Peak 1, and Compound 312, Peak 2)

Methyl 3- (3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)-[1, 1'-biphenyl] -3-yl) -2-methylpropanol (74.0 mg) is a chiral preparative HPLC: CHIRALPAK IF-3, 20 ^* 250 mm, 5 um; Phase A: EtOH (0.2% THF). ); Phase B: THF; 15% B, 8 minutes; separated by 20 ml / min. As a result, as a white solid, methyl 3- (3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5) -Il)-[1,1'-biphenyl] -3-yl) -2-methylpropanoate, peak 1 (Compound 311-A), 15 mg, and peak 2 (Compound 312-A) as a white solid. ), 13 mg was obtained.

Data for compound 311-A (peak 1): chiral HPLC (CHIRALPAK IF-3, 100x4.6 mm, 3 μm, 0.8 mL / min, 20% B). A: Ethanol (0.1% THF); B: THF: t _R = 2.87 minutes. ^* The absolute stereochemistry of a single isolated enantiomer is not determined.

Data for compound 312-A (peak 2): chiral HPLC (CHIRALPAK IF-3, 100x4.6 mm, 3 μm, 0.8 mL / min, 20% B). A: Ethanol (0.1% THF); B: THF: t _R = 3.48 minutes. ^* The absolute stereochemistry of a single isolated enantiomer is not determined.

Methyl 3- (3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-) in MeOH (1.0 mL) 5-yl)-[1,1'-biphenyl] -3-yl) -2-methylpropanol, Peak 1 (Compound 311-A) (15.0 mg, 0.035 mmol, 1.00 eq) and 2M The solution of NaOH (0.30 mL) was stirred at room temperature for 2 hours. The mixture was acidified to pH 5-6 with FA. By purifying the mixture by preparative HPLC, 3- (3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,2,3] triazolo [4,2,3] triazolo [4,2,3] triazolo [4,2,3] 5-d] Pyrimidine-5-yl)-[1,1'-biphenyl] -3-yl) -2-methylpropanoic acid (4.0 mg, 26%) was obtained.

Data for compound 311: LCMS (ESI) = 420.1 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ8.02 (d, J = 8.5 Hz, 1H), 7.64-7.56 (m, 2H), 7.46-7.33 (m, 3H) ), 7.25 (d, J = 7.5Hz, 1H), 4.32 (q, J = 6.9Hz, 2H), 3.08-2.94 (m, 1H), 2.70 (s). , 1H), 2.53 (s, 1H), 1.43 (t, J = 6.9Hz, 3H), 1.09 (d, J = 6.2Hz, 3H). Chiral HPLC (CHIRALPAK IC-3, 4.6 ^* 50 mm, 3 μm, 1 mL / min, 12.5 min, 10% B). A: Ethanol (0.5% TFA); B: n-hexane / DCM, 3: 1: t _R = 6.45 minutes. ^* The absolute stereochemistry of a single isolated enantiomer is not determined.

3- (3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)-[1,1 '-Biphenyl] -3-yl) -2-methylpropionic acid, Peak 2 (Compound 312) is prepared using the same procedure used for Compound 311 to make 3- (3'-ethoxy-4). '-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)-[1,1'-biphenyl] -3-yl) -2-Methylpropionic acid, peak 2 (compound 312) was obtained.

Data for compound 312: Chiral HPLC (CHIRALPAK IC-3, 4.6 ^* 50 mm, 3 μm, 1 mL / min, 12.5 min, 10% B). A: Ethanol (0.5% TFA); B: n-hexane: DCM 3: 1: t _R = 7.50 minutes. ^* The absolute stereochemistry of a single isolated enantiomer is not determined.

Examples 149: 3- (3'-ethoxy-4-isopropoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-) Separation of enantiomers of 5-yl)-[1,1'-biphenyl] -3-yl) -2-methylpropanoic acid (Compound 313, Peak 1, and Compound 314, Peak 2)

3- (3'-ethoxy-4-isopropoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl) -[1,1'-biphenyl] -3-yl) -2-methylpropanoic acid were individually prepared using the procedure of Example 83, except that the preparative CHIRALPAK IG-3 column was used for separation. Isolated on the enantiomer.

Data for compound 313 (peak 1): LCMS (ESI) = 478.2 [M + H] ⁺ . Chiral HPLC (CHIRALPAK IG-3, 100 ^* 4.6 mm, 3 μm, 1 mL / min, 20% B). A: n-hexane: DCM 4/1; B: ethanol (0.5% FA): t _R = 3.09 minutes. ^* The absolute stereochemistry of a single isolated enantiomer is not determined.

Data for compound 314 (peak 2): LCMS (ESI) = 478.2 [M + H] ⁺ . Chiral HPLC: t _R = 3.79 minutes. ^* The absolute stereochemistry of a single isolated enantiomer is not determined.

Example 150: (E) -3- (3'-ethoxy-4-methoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] ] Pyrimidine-5-yl)-[1,1'-biphenyl] -3-yl) -2-methylacrylic acid (Compound 315) synthesis

(E) -3- (3'-ethoxy-4-methoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5 -Il)-[1,1'-biphenyl] -3-yl) -2-methylacrylic acid was prepared using the procedure of Example 138. LCMS (ESI) = 448.1 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ12.13 (s, 1H), 7.87 (d, J = 8.5 Hz, 1H), 7.84-7.76 (m, 1H), 7. 72 (dd, J = 4.6, 2.1Hz, 2H), 7.44-7.35 (m, 2H), 7.20 (d, J = 8.7Hz, 1H), 4.31 (q) , J = 7.0Hz, 2H), 3.89 (s, 3H), 2.00 (d, J = 1.5Hz, 3H), 1.40 (t, J = 6.9Hz, 3H).

Examples 151: 3- (3'-ethoxy-4-methoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5 -Il)-[1,1'-biphenyl] -3-yl) -2-Methylpropionic acid (Compound 316) synthesis

3- (3'-ethoxy-4-methoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)- [1,1'-Biphenyl] -3-yl) -2-methylpropionic acid was prepared using the procedure of Example 139. LCMS (ESI) = 450.2 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ7.93 (d, J = 8.4 Hz, 1H), 7.64 (dd, J = 8.9, 2.5 Hz, 1H), 7.55 (d) , J = 2.4Hz, 1H), 7.39-7.30 (m, 2H), 7.08 (d, J = 8.6Hz, 1H), 4.31 (q, J = 6.8Hz, 2H), 3.85 (s, 3H), 2.94 (s, 1H), 2.80-2.64 (m, 2H), 1.42 (t, J = 6.9Hz, 3H), 1 .07 (d, J = 6.2Hz, 3H).

Example 152: (E) -3- (3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidine-5) -Synthesis of -4- (2- (pyrrolidin-1-yl) ethoxy)-[1,1'-biphenyl] -3-yl) acrylic acid (Compound 317)

Step 1: 5-bromo-2-hydroxybenzaldehyde (3.50 g, 17.4 mmol, 1.00 eq) and ethyl 2- (triphenyl-λ ⁵ -phosphanylidene) acetate (9.10 g,) in DCM (40 mL), The solution (26.5 mmol, 1.5 eq) was stirred at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure. The residue is purified by silica gel column chromatography and eluted with EA / PE (0-30%) to form an ethyl (E) -3- (5-bromo-2-hydroxyphenyl) acrylate (4. 0 g, 76.3%) was obtained. ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ10.55 (s, 1H), 7.85-7.72 (m, 2H), 7.69-7.46 (m, 1H), 7.34 ( dd, J = 8.7, 2.5Hz, 1H), 6.88 (d, J = 8.7Hz, 1H), 6.65 (d, J = 16.2Hz, 1H), 4.16 (q) , J = 7.1Hz, 2H), 1.23 (t, J = 7.1Hz, 3H).

Step 2: Ethyl (E) -3- (5-bromo-2-hydroxyphenyl) acrylate (500 mg, 1.84 mmol) in DMF (10 mL) and K ₂ CO ₃ (510 mg, 3.69 mmol, 2.00 eq). , 1.00 eq) and 1- (2-chloroethyl) pyrrolidine (271 mg, 2.03 mmol, 1.1 eq) were stirred at 80 ° C. for 3 hours. The resulting mixture was diluted with water (40 mL). The resulting mixture was extracted with EA (3x40 mL). The combined organic layer was washed with brine (2x40 mL) and dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue is purified by silica gel column chromatography and eluted with MeOH / DCM (0-20%) to give ethyl (E) -3- (5-bromo-2- (2- (pyrrolidin-1)) as a yellow solid. -Il) ethoxy) phenyl) acrylate (500 mg, 66.3%) was obtained. ^{1 1} H NMR (300 MHz, CDCl ₃ ) δ7.92 (d, J = 16.2 Hz, 1H), 7.63 (d, J = 2.5 Hz, 1H), 7.42 (dd, J = 8.8) , 2.5Hz, 1H), 6.81 (d, J = 8.8Hz, 1H), 6.51 (d, J = 16.2Hz, 1H), 4.27 (q, J = 7.2Hz, 2H), 4.17 (t, J = 6.0Hz, 2H), 2.99 (t, J = 6.0Hz, 2H), 2.75-2.62 (m, 4H), 1.93- 1.76 (m, 4H), 1.34 (t, J = 7.2Hz, 3H).

Step 3: Ethyl (E) -3- (5-bromo-2- (2- (pyrrolidin-1-yl) ethoxy) phenyl) acrylate in dioxane (5.00 mL) (500 mg, 1.36 mmol, 1.00 mL) KOAc (266 mg, 2.72 mmol, 2.0 eq) and Pd (dpppf) Cl ₂ (99.3 mg, 99.3 mg,) in a stirred solution of bis (pinacholate) diboron (414 mg, 1.63 mmol, 1.2 eq). 0.136 mmol, 0.1 eq) were added in several portions at room temperature. The resulting mixture was stirred at 100 ° C. for 2 hours. The mixture was purified by silica gel column chromatography and eluted with MeOH / DCM (0-20%) to give ethyl (E) -3- (2- (2- (pyrrolidin-1-yl) ethoxy) as a gray oil. -5- (4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) acrylate (400 mg, 66.1%) was obtained. (E) -3- (3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)- 4- (2- (Pyrrolidine-1-yl) ethoxy)-[1,1'-biphenyl] -3-yl) acrylic acid was prepared using the procedures of Examples 1 and 9. LCMS (ESI) = 517.3 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ11.70 (s, 1H), 8.10 (d, J = 2.4 Hz, 1H), 7.97-7.86 (m, 2H), 7. 81 (dd, J = 8.7, 2.3Hz, 1H), 7.46 (s, 1H), 7.24 (d, J = 8.8Hz, 1H), 6.81 (d, J = 16) .1Hz, 1H), 4.36 (d, J = 6.8Hz, 1H), 4.30 (t, J = 7.2Hz, 3H), 3.05 (t, J = 5.6Hz, 2H) , 2.74 (d, J = 12.2Hz, 1H), 2.74 (s, 3H), 1.84-1.71 (m, 4H), 1.42 (t, J = 6.9Hz, 3H.

Example 153: 3- (3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)- Synthesis of 4- (2- (pyrrolidin-1-yl) ethoxy)-[1,1'-biphenyl] -3-yl) propanoic acid (Compound 318)

3- (3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidine-5-yl) -4- (2) -(Pyrrolidine-1-yl) ethoxy)-[1,1'-biphenyl] -3-yl) propionic acid was prepared using the procedure of Example 139. LCMS (ESI) = 519.2 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ11.49 (s, 1H), 7.94 (d, J = 8.5 Hz, 1H), 7.64-7.55 (m, 2H), 7. 35 (d, J = 6.5Hz, 2H), 7.08 (d, J = 9.2Hz, 1H), 4.31 (q, J = 6.9Hz, 2H), 4.19 (t, J) = 5.6Hz, 2H), 2.99 (t, J = 5.5Hz, 2H), 2.90 (t, J = 7.6Hz, 2H), 2.76-2.67 (m, 4H) , 2.56 (d, J = 7.5Hz, 2H), 1.75 (p, J = 3.2Hz, 4H), 1.42 (t, J = 6.9Hz, 3H).

Example 154: (E) -3- (4- (2- (dimethylamino) ethoxy) -3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] ] Triazolo [4,5-d] pyrimidin-5-yl)-[1,1'-biphenyl] -3-yl) Synthesis of acrylic acid (Compound 319)

(E) -3- (4- (2- (dimethylamino) ethoxy) -3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4] , 5-d] Pyrimidine-5-yl)-[1,1'-biphenyl] -3-yl) acrylic acid was prepared using the procedure of Example 152. LCMS (ESI) = 491.3 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ11.67 (s, 1H), 8.10 (d, J = 2.3 Hz, 1H), 7.98-7.84 (m, 2H), 7. 83 (dd, J = 8.7, 2.4Hz, 1H), 7.46 (dd, J = 4.5, 2.9Hz, 2H), 7.24 (d, J = 8.8Hz, 1H) , 6.81 (d, J = 16.1Hz, 1H), 4.35 (q, J = 6.9Hz, 2H), 4.25 (t, J = 5.6Hz, 2H), 2.80 ( t, J = 5.6Hz, 2H), 2.32 (s, 6H), 1.42 (t, J = 6.9Hz, 3H).

Example 155: 3- (4- (2- (dimethylamino) ethoxy) -3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4] , 5-d] Pyrimidine-5-yl)-[1,1'-biphenyl] -3-yl) Propionic acid (Compound 320) synthesis

3- (4- (2- (dimethylamino) ethoxy) -3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] ] Pyrimidine-5-yl)-[1,1'-biphenyl] -3-yl) propionic acid was prepared using the procedure of Example 139. LCMS (ESI) = 493.2 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ7.93 (d, J = 8.0 Hz, 1H), 7.55 (dq, J = 3.9, 2.4 Hz, 2H), 7.32 (d) , J = 1.6Hz, 1H), 7.29 (s, 1H), 7.03 (d, J = 9.2Hz, 1H), 3.10 (s, 2H), 2.88 (s, 2H) ), 2.55 (s, 6H), 2.44 (t, J = 7.2Hz, 2H), 1.39 (t, J = 6.9Hz, 3H).

Examples 156: 3- (3'-ethoxy-4-methyl-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5 -Il)-[1,1'-biphenyl] -3-yl) Propionic acid (Compound 321) synthesis

3- (3'-ethoxy-4-methyl-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)- [1,1'-biphenyl] -3-yl) propionic acid was prepared using the method described in the previous example. LCMS (ESI) = 420.1 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ7.95 (d, J = 8.4 Hz, 1H), 7.58 (d, J = 2.0 Hz, 1H), 7.52 (dd, J = 7) 8.8, 2.0Hz, 1H), 7.38 (dt, J = 4.5, 2.2Hz, 2H), 7.27 (d, J = 7.9Hz, 1H), 4.31 (q, J = 6.8Hz, 2H), 2.91 (t, J = 7.8Hz, 2H), 2.58 (dd, J = 8.6, 7.0Hz, 2H), 2.34 (s, 3H) ), 1.42 (t, J = 6.9Hz, 3H).

Example 157: (E) -3- (3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidine-5) -Synthesis of -yl) -6- (2- (pyrrolidin-1-yl) ethoxy)-[1,1'-biphenyl] -3-yl) acrylic acid (Compound 322)

(E) -3- (3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)- 6- (2- (Pyrrolidine-1-yl) ethoxy)-[1,1'-biphenyl] -3-yl) acrylic acid is 3-bromo-using the method described in the previous example. Prepared from 4-hydroxybenzaldehyde. LCMS (ESI) = 517.2 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ12.04 (s, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.75 (d, J = 6.9 Hz, 2H), 7.64 (d, J = 15.9Hz, 1H), 7.40-7.30 (m, 2H), 7.24 (d, J = 9.1Hz, 1H), 6.51 (d, J) = 16.0Hz, 1H), 4.32-4.19 (m, 4H), 3.05 (s, 2H), 2.76-2.70 (m, 4H), 1.76-1.70 (M, 4H), 1.40 (t, J = 6.9Hz, 3H).

Example 158: 3- (3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)- Synthesis of 6- (2- (pyrrolidin-1-yl) ethoxy)-[1,1'-biphenyl] -3-yl) propanoic acid (Compound 323)

3- (3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidine-5-yl) -6- (2) -(Pyrrolidine-1-yl) ethoxy)-[1,1'-biphenyl] -3-yl) propionic acid was prepared using the method described in the previous example. LCMS (ESI) = 519.2 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ11.89 (s, 1H), 7.86 (d, J = 8.1 Hz, 1H), 7.36-7.20 (m, 4H), 7. 09 (d, J = 8.4Hz, 1H), 4.30-4.13 (m, 4H), 3.01-2.95 (m, 2H), 2.84 (t, J = 7.5Hz) , 2H), 2.72-2.66 (m, 4H), 2.62-2.51 (m, 2H), 1.75-1.69 (m, 4H), 1.40 (t, J) = 6.9Hz, 3H).

Example 159: (E) -3- (3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidine-5) -Il) -5- (2- (Pyrrolidine-1-yl) ethoxy)-[1,1'-biphenyl] -3-yl) Acrylic acid (Compound 324) synthesis

(E) -3- (3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)- 5- (2- (Pyrrolidine-1-yl) ethoxy)-[1,1'-biphenyl] -3-yl) acrylic acid is 3-bromo-using the method described in the previous example. Prepared from 5-hydroxybenzaldehyde. LCMS (ESI) = 517.4 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ11.84 (roads, 1H), 7.92 (d, J = 8.4 Hz, 1H), 7.74-7.62 (m, 2H), 7 .49 (dd, J = 4.5, 2.9Hz, 2H), 7.38 (s, 2H), 6.74 (d, J = 16.0Hz, 1H), 4.40-4.26 ( m, 4H), 3.10 (d, J = 5.5Hz, 2H), 2.83 (s, 4H), 1.79 (t, J = 3.7Hz, 4H), 1.41 (t, J = 6.9Hz, 3H).

Example 160: 3- (3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-yl)- Synthesis of 5- (2- (pyrrolidin-1-yl) ethoxy)-[1,1'-biphenyl] -3-yl) propanoic acid (Compound 325)

3- (3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] pyrimidine-5-yl) -5- (2) -(Pyrrolidine-1-yl) ethoxy)-[1,1'-biphenyl] -3-yl) propionic acid was prepared using the method described in the previous example. LCMS (ESI) = 519.4 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ11.92 (s, 1H), 8.15 (s, 0H), 7.90 (d, J = 8.4 Hz, 1H), 7.44-7. 35 (m, 2H), 7.26 (s, 1H), 7.15 (d, J = 2.2Hz, 1H), 6.92 (s, 1H), 4.38-4.22 (m, 4H), 3.19 (t, J = 5.4Hz, 2H), 2.96-2.84 (m, 6H), 2.62 (t, J = 7.7Hz, 2H), 1.88- 1.78 (m, 4H), 1.41 (t, J = 6.9Hz, 3H).

Examples 161: (E) -3- (6- (2- (dimethylamino) ethoxy) -3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] ] Triazolo [4,5-d] pyrimidin-5-yl)-[1,1'-biphenyl] -3-yl) Acrylic acid (Compound 326) synthesis

(E) -3- (6- (2- (dimethylamino) ethoxy) -3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4] , 5-d] Pyrimidine-5-yl)-[1,1'-biphenyl] -3-yl) acrylic acid was prepared using the method described in the previous example. LCMS (ESI) = 491.2 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ12.04 (s, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.75 (d, J = 8.3 Hz, 2H), 7.63 (d, J = 16.0Hz, 1H), 7.41 (d, J = 1.5Hz, 1H), 7.35 (dd, J = 8.1, 1.5Hz, 1H), 7 .24 (d, J = 8.4Hz, 1H), 6.51 (d, J = 16.0Hz, 1H), 4.33-4.18 (m, 4H), 2.79 (t, J = 5.5Hz, 2H), 2.30 (s, 6H), 1.40 (t, J = 6.9Hz, 3H).

Examples 162: 3- (6- (2- (dimethylamino) ethoxy) -3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4] , 5-d] Pyrimidine-5-yl)-[1,1'-biphenyl] -3-yl) Propionic acid (Compound 327) synthesis

3- (6- (2- (dimethylamino) ethoxy) -3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] ] Pyrimidine-5-yl)-[1,1'-biphenyl] -3-yl) propionic acid was prepared using the method described in the previous example. LCMS (ESI) = 493.2 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ11.97 (s, 1H), 7.86 (d, J = 8.1 Hz, 1H), 7.37 (d, J = 1.5 Hz, 1H), 7.32-7.19 (m, 3H), 7.09 (d, J = 8.4Hz, 1H), 4.24 (q, J = 6.9Hz, 2H), 4.14 (t, J) = 5.6Hz, 2H), 2.82 (dt, J = 8.2,6.5Hz, 4H), 2.56 (t, J = 7.5Hz, 2H), 2.32 (s, 6H) , 1.40 (t, J = 6.9Hz, 3H).

Example 163: (E) -3- (5- (2- (dimethylamino) ethoxy) -3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] ] Triazolo [4,5-d] pyrimidin-5-yl)-[1,1'-biphenyl] -3-yl) Synthesis of acrylic acid (Compound 328)

(E) -3- (5- (2- (dimethylamino) ethoxy) -3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4] , 5-d] Pyrimidine-5-yl)-[1,1'-biphenyl] -3-yl) acrylic acid was prepared using the method described in the previous example. LCMS (ESI) = 491.4 [M + H] ⁺ .

Examples 164: 3- (5- (2- (dimethylamino) ethoxy) -3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4] , 5-d] Pyrimidine-5-yl)-[1,1'-biphenyl] -3-yl) Propionic acid (Compound 329) synthesis

3- (5- (2- (dimethylamino) ethoxy) -3'-ethoxy-4'-(7-oxo-6,7-dihydro-3H- [1,2,3] triazolo [4,5-d] ] Pyrimidine-5-yl)-[1,1'-biphenyl] -3-yl) propionic acid was prepared using the method described in the previous example. LCMS (ESI) = 493.3 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ11.94 (s, 1H), 7.89 (d, J = 8.4 Hz, 1H), 7.40 (dq, J = 3.1, 1.6 Hz) , 2H), 7.24 (d, J = 1.5Hz, 1H), 7.14 (t, J = 2.0Hz, 1H), 6.94-6.87 (m, 1H), 4.31 (Q, J = 6.9Hz, 2H), 4.22 (t, J = 5.5Hz, 2H), 2.90 (q, J = 7.9, 6.6Hz, 4H), 2.62 ( t, J = 7.6Hz, 2H), 2.43 (s, 6H), 1.41 (t, J = 6.9Hz, 3H).

Example 165: β-Arrestin Assay

Human GPR35 expressing TangoU2OS cells was sown in a clear bottom plate at a cell density of 10,000 cells / well in a 384-well format and grown overnight. The next day, cells were treated with continuously diluted test compound for 5 hours. Then, LiveBlazer-FRET B / G (CCF4-AM) detection reagent was added, and after incubating for 2 hours, the plates were read with a BioTek Cytation 5 plate reader. Zaprinast was used as a positive control for the dose-response curve. Data were fitted to a 4-parameter dose-response curve to determine the _EC50 value. The _EC50 values are shown in Table 1.

Example 166: Alternative β-arrestin assay JumpIn (Thermo Fisher) 294R Human GPR35 expressing TangoU2OS cells is sown in a clear bottom plate at a cell density of 10,000 cells / well in a 384-well format and grown overnight. I let you. The next day, cells were treated with continuously diluted test compound for 5 hours. Then, LiveBlazer-FRET B / G (CCF4-AM) detection reagent was added, and after incubating for 2 hours, the plates were read with a BioTek Cytation 5 plate reader. Zaprinast was used as a positive control for the dose-response curve. Data were fitted to a 4-parameter dose-response curve to determine the _EC50 value. The _EC50 values are shown in Table 2.

Example 167. Phase I / II clinical trial of mild to moderate ulcerative colitis

Double-blind, randomized to assess the safety, tolerability, and pilot therapeutic activity of compound formula (I), (I'), or (I'') (“Compound”). , A placebo-controlled clinical trial was conducted. Subjects with mild to moderate ulcerative colitis are orally administered the compound as a capsule for 6 weeks.

Eligible subjects are each randomly assigned either compound or placebo. Initial treatment A sigmoidoscopy with a biopsy will be performed at the time of visit and at 6 weeks. Subjects are treated for 12 weeks and clinical evaluation is performed between the 2nd, 4th, 6th, and 10-12 weeks.

Inclusion criteria:
1. 1. The subject has a proven diagnosis of mild to moderate ulcerative colitis, as evidenced clinically and endoscopically at the second visit.
2. 2. Baron score of 2 or higher at baseline.
3. 3. Truelove-Witt (modified) score is 14 or less.
4. Duration of illness of 4.6 months or more 5. At baseline, the subject must have a stable disease or a stable disease requiring 5-ASA treatment.
During 6.5-ASA treatment, subjects must have been administered at a stable dose for at least 2 weeks prior to screening and will continue to do so until the end of the study.
7. Subject has key organs (excluding the gastrointestinal tract) that function normally, as indicated by medical history, vital signs, physical examination, and laboratory tests (including blood, coagulation, chemistry, and urinalysis). That you are.
8. Male or female subjects aged 18-70 years 9. Subject has voluntary written informed consent to participate in this study.
10. Subject may be pregnant, but has not planned to become pregnant, breastfeeding, or pregnant during the study period and has a negative pre-registration pregnancy test.
11. Subjects agree to perform a medically acceptable form of contraception from screening to 30 days after the final dose of study drug. Female partners of male subjects enrolled in this study are also recommended to use acceptable contraceptive methods. Men must agree not to donate sperm for the entire duration of the study and for 90 days after the final dose of study drug.

Exclusion criteria:
1. 1. In the opinion of the investigator, a clinically significant medical history that may threaten the safety of the subject, affect the validity of the study results, or prevent the completion of treatment according to this protocol. Medical findings, or ongoing medical or mental illness.
2. 2. The subject has ALT or serum creatinine above 1.5 times the upper limit of the normal range of the reference laboratory at the time of screening.
3. 3. Subjects who the investigator determined to have a fever during screening.
4. Subjects treated with IBD as follows: steroids or any or biological immunomodulators within the last 4 weeks prior to baseline, or topical treatment (such as enema), immunosuppression within the last 6 weeks Have used an agent or antimetabolite, antibiotics within the last 7 days, or chronic use of anti-inflammatory agents (excluding aminosalicylate) within 7 days.
5. A history of illicit substance abuse, a positive urinalysis of the substance of abuse, or a history of alcohol abuse (if confirmed at the screening visit or listed in the subject's medical records at the time of screening).
6. The subject is positive on a blood test for either HIV, hepatitis B (HBsAg), or hepatitis C.
7. Subject has evidence of infectious colitis, such as Clostridium difficile, amebiasis, Giardia lamblia, on a stool test at screening.
8. Subject has evidence of gastrointestinal parasites on stool test at screening.
9. Subjects have evidence of tuberculosis by blood interferon gamma release assay at screening.
10. Uncontrolled ongoing illness (eg, active infection).
11. History of gastrointestinal cancer.
12. Abdominal surgery or major surgery within 28 days prior to screening visit.

Primary endpoint: Safety and tolerability of the compound in subjects with ulcerative colitis, indicated by the frequency and severity of adverse events [timeframe: 6 weeks].

Secondary endpoint:
1. 1. Changes in Modified Baron Score from baseline to 6 weeks [time frame: 6 weeks].
2. 2. Changes in ulcerative colitis clinical score from baseline [time frame: 6 weeks].
3. 3. Partial Mayo score change from baseline [timeframe: 6 weeks].
4. Calprotectin concentration [time frame: 6 weeks].
5. Riley Acute Inflammation Scale (histological) [time frame: 6 weeks].
6. Clinical remission [time frame: 6 weeks].

Example 168: Treatment of a subject with ulcerative colitis

Subjects diagnosed with mild to moderate ulcerative colitis (UC) are compound formula (I), (I'), or, as shown clinically and by endoscopy at the second visit. (I'') (hereinafter, “compound”) is treated. The compound is administered intravenously or orally at least once, and optionally multiple times a week. After a period of time (eg, 6 weeks), the subject may show relief of UC-related symptoms such as external bleeding, hemorrhagic diarrhea, abdominal pain, or pain. In addition, subjects may show a decrease in modified Baron score, ulcerative colitis clinical score, partial Mayo score (endoscopic), or Riley acute inflammation scale (histological). In some cases, the subject exhibits clinical remission. In some cases, biomarkers such as calprotectin levels measured in fecal samples taken from subjects after treatment are reduced compared to baseline (collected before treatment).

The embodiments and embodiments described herein are for illustrative purposes only, and in some embodiments, various modifications or modifications are within the scope of this disclosure and the accompanying claims. do.

Claims (54)

A compound having the structure of formula (I''), or a pharmaceutically acceptable salt or solvate thereof.

During the ceremony
R ¹ is -CH ₂ R ⁴ , -CN, -B (OH) ₂ , -N (R ¹⁰ ) ₂ , -NR ¹⁰ C (O) R ⁹ , -C (O) OH, -CH ₂ C ( O) OH, -C (O) N (R ¹⁰ ) ₂ , -C (O) NHS (O) ₂ N (R ¹⁰ ) ₂ , -C _1-6 alkyl-OH, C _3-8 cycloalkyl,

Or a 5- or ⁶ -membered heteroaryl optionally substituted with one, two, or three R8 groups.
R ² is H, -OH, -N (R ¹⁰ ) ₂ , -NHS (O) ₂ R ⁹ , -S (O) ₂ N (R ¹⁰ ) ₂ , -C (O) N (R ¹⁰ ) ₂ , -OC (O) N (R ¹⁰ ) ₂ , -OC _1-6 alkyl, -C _1-6 alkyl-OH, -C _1-6 alkyl-OR ⁹ , -C _1-6 alkyl-N ( R ¹⁰ ) ₂ , C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _3-8 cycloalkyl.
R ³ are independently halogen, -CN, -OH, -OR ⁹ , -SR ⁹ , -N (R ¹⁰ ) ₂ , -NO ₂ , -S (O) R ⁹ , -S (O) ₂ . R ⁹ , -NHS (O) ₂ R ⁹ , -S (O) ₂ N (R ¹⁰ ) ₂ , -C (O) R ⁹ , -C (O) OR ¹⁰ , -OC (O) R ⁹ ,- C (O) N (R ¹⁰ ) ₂ , -OC (O) N (R ¹⁰ ) ₂ , -NR ¹⁰ C (O) N (R ¹⁰ ) ₂ , -NR ¹⁰ C (O) R ⁹ , -NR ¹⁰ C (O) OR ⁹ , C _1-6 alkyl, -C _1-6 alkyl-OH, -C _1-6 alkyl-OR ⁹ , -C _1-6 alkyl-N (R ¹⁰ ) ₂ , C _2-6 Selected from alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, and -C _1-6 alkyl-C _3-8 cycloalkyl.
^R4 is

And
R ⁵ are independently halogen, -CN, -OH, -OR ⁹ , -SR ⁹ , -N (R ¹⁰ ) ₂ , -S (O) R ⁹ , -S (O) ₂ R ⁹ ,- NHS (O) ₂ R ⁹ , -S (O) ₂ N (R ¹⁰ ) ₂ , -C (O) NHS (O) ₂ N (R ¹⁰ ) ₂ , -C (O) R ⁹ , -C (O) ) OR ¹⁰ , -OC (O) R ⁹ , -C (O) N (R ¹⁰ ) ₂ , -OC (O) N (R ¹⁰ ) ₂ , -NR ¹⁰ C (O) N (R ¹⁰ ) ₂ , -NR ¹⁰ C (O) R ⁹ , -NR ¹⁰ C (O) OR ⁹ , C _1-6 alkyl, -C _1-6 alkyl-R ⁹ , -C _1-6 alkyl-OH, -C _1-6 Alkyl-OR ⁹ , -C _1-6 Alkyl-N (R ¹⁰ ) ₂ , -C _1-6 Alkyl-C (O) OR ¹⁰ , C _2-6 Alkenyl, -C _2-6 Alkenyl-C (O) OR ¹⁰ , C _2-6 alkynyl, C _1-6 haloalkyl, C _1-6 haloalkyl-OH, C _3-8 cycloalkyl, -C _1-6 alkyl-C _3-8 cycloalkyl, phenyl, -C _1- Selected from ₆ Alkyl-Phenyl, C _2-9 Heterocycloalkyl, -C _1-6 Alkyl-C _2-9 Heterocycloalkyl, and C _1-9 Heteroaryl; where C _3-8 Cycloalkyl,- C _1-6 alkyl-C _3-8 cycloalkyl, phenyl, -C _1-6 alkyl-phenyl, and C _1-9 heteroaryl are halogen, -C (O) OR ¹⁰ , C _1-6 alkyl, C. Arbitrarily substituted with one, two, or three groups independently selected from _1-6 haloalkyl, C _3-8 cycloalkyl, and C _2-9 heterocycloalkyl; and where C _{2- 9} Heterocycloalkyl and -C 1-6alkyl-C _2-9 Heterocycloalkyl are selected independently of halogen, -C (O) OR ¹⁰ , C _{1-6 alkyl, C 1-6 haloalkyl} , and oxo. Is optionally substituted with one, two, or three groups,
R ⁶ is -C (O) OR ⁷ , -C (O) NHS (O) ₂ N (R ¹⁰ ) ₂ ,

And
^R7 is independently selected from H and C _1-6 alkyl
R ⁸ are independently halogen, -OH, -OR ⁹ , -N (R ¹⁰ ) ₂ , -S (O) R ⁹ , -S (O) ₂ R ⁹ , -NHS (O) ₂ R ⁹ , -S (O) ₂ N (R ¹⁰ ) ₂ , -C (O) NHS (O) ₂ N (R ¹⁰ ) ₂ , -C (O) R ⁹ , -C (O) OR ¹⁰ , -OC ( O) R ⁹ , -C (O) N (R ¹⁰ ) ₂ , -OC (O) N (R ¹⁰ ) ₂ , -NR ¹⁰ C (O) N (R ¹⁰ ) ₂ , -NR ¹⁰ C (O) R ⁹ , -NR ¹⁰ C (O) OR ⁹ , C _1-6 alkyl, -C _1-6 alkyl-OH, -C _1-6 alkyl-OR ⁹ , -C _1-6 alkyl-N (R ¹⁰ ) ₂ , -C _1-6 alkyl-C (O) OR ¹⁰ , C _1-6 haloalkyl, C _1-6 haloalkyl-OH, C _3-8 cycloalkyl, -C _1-6 alkyl-C _3-8 cycloalkyl , Phenyl, -C _1-6 alkyl-phenyl, C _2-9 heterocycloalkyl, and C _1-9 heteroaryl; where phenyl, -C _1-6 alkyl-phenyl, and C _1-9 Heteroaryl is one, two or three groups independently selected from halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, and C _2-9 heterocycloalkyl. And where the C _2-9 heterocycloalkyl is selected independently of halogen, C _1-6 alkyl, C _1-6 haloalkyl, and oxo, one, two, or three. Arbitrarily replaced by one group,
R ⁹ are independently C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, -C _1-6 alkyl-C _3-8 cycloalkyl, phenyl, -C _1-6 alkyl- Selected from phenyl, C _2-9 heterocycloalkyl, -C _1-6 alkyl-C _2-9 heterocycloalkyl, C _2-9 heteroaryl, and -C _1-6 alkyl-C _2-9 heteroaryl, Here, C _1-6 alkyl, phenyl, -C _1-6 alkyl-phenyl, -C _1-6 alkyl-C _2-9 heterocycloalkyl, C _2-9 heteroaryl, and -C _1-6 alkyl- C _2-9 heteroaryls are C _1-6 alkyl, -OR ¹¹ , -N (R ¹¹ ) ₂ , C _1-6 alkyl, C _3-8 cycloalkyl, -N (R ¹¹ ) C (O) R. It is optionally substituted with one or two groups independently selected from ¹² , -C (O) R ¹² , and -C (O) OR ¹² .
R ¹⁰ are independently H, C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, -C _1-6 alkyl-C _3-8 cycloalkyl, phenyl, -C _1-6 . Selected from alkyl-phenyl and C _2-9 heteroaryl, where C _1-6 alkyl, phenyl, -C _1-6 alkyl-phenyl, and C _2-9 heteroaryl are halogen, C _1-6 . It is optionally substituted with one or two groups independently selected from alkyl, -N (R ¹¹ ) ₂ , and -C (O) OR ¹² ; or two R ^10s , and they are combined. The nitrogen atoms present together are 5-membered or optionally substituted with one, two, or three groups independently selected from C _1-6 alkyl, oxo, and -C (O) OH. Forming a 6-membered heterocycloalkyl ring,
R ¹¹ is independently selected from H and C _1-6 alkyl, respectively.
R ¹² is independently selected from H and C _1-6 alkyl, respectively.
Each of R ¹³ is independently selected from C _1-6 alkyl.
m is 1, 2, 3, or 4,
n is 0, 1, 2, or 3
p is 0, 1, 2, 3, 4, or 5, and
q is 0, 1, 2, 3, or 4,
A compound, or a pharmaceutically acceptable salt or solvate thereof. A compound having the structure of formula (I'), or a pharmaceutically acceptable salt or solvate thereof.

During the ceremony
R ¹ is -CH ₂ R ⁴ , -CN, -B (OH) ₂ , -N (R ¹⁰ ) ₂ , -NR ¹⁰ C (O) R ⁹ , -C (O) OH, -CH ₂ C ( O) OH, -C (O) N (R ¹⁰ ) ₂ , -C (O) NHS (O) ₂ N (R ¹⁰ ) ₂ , -C _1-6 alkyl-OH, C _3-8 cycloalkyl,

Alternatively, it is a 5- or ⁶ -membered heteroaryl optionally substituted with one, two, or three R8 groups.
R ² is H, -OH, -N (R ¹⁰ ) ₂ , -NHS (O) ₂ R ⁹ , -S (O) ₂ N (R ¹⁰ ) ₂ , -C (O) N (R ¹⁰ ) ₂ , -OC (O) N (R ¹⁰ ) ₂ , -OC _1-6 alkyl, -C _1-6 alkyl-OH, -C _1-6 alkyl-OR ⁹ , -C _1-6 alkyl-N ( R ¹⁰ ) ₂ , C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _3-8 cycloalkyl.
R ³ are independently halogen, -CN, -OH, -OR ⁹ , -SR ⁹ , -N (R ¹⁰ ) ₂ , -S (O) R ⁹ , -S (O) ₂ R ⁹ ,- NHS (O) ₂ R ⁹ , -S (O) ₂ N (R ¹⁰ ) ₂ , -C (O) R ⁹ , -C (O) OR ¹⁰ , -OC (O) R ⁹ , -C (O) N (R ¹⁰ ) ₂ , -OC (O) N (R ¹⁰ ) ₂ , -NR ¹⁰ C (O) N (R ¹⁰ ) ₂ , -NR ¹⁰ C (O) R ⁹ , -NR ¹⁰ C (O) OR ⁹ , C _1-6 alkyl, -C _1-6 alkyl-OH, -C _1-6 alkyl-OR ⁹ , -C _1-6 alkyl-N (R ¹⁰ ) ₂ , C _2-6 alkenyl, C ₂ Selected from _-6 alkynyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, and -C _1-6 alkyl-C _3-8 cycloalkyl.
^R4 is

And
R ⁵ are independently halogen, -CN, -OH, -OR ⁹ , -SR ⁹ , -N (R ¹⁰ ) ₂ , -S (O) R ⁹ , -S (O) ₂ R ⁹ ,- NHS (O) ₂ R ⁹ , -S (O) ₂ N (R ¹⁰ ) ₂ , -C (O) NHS (O) ₂ N (R ¹⁰ ) ₂ , -C (O) R ⁹ , -C (O) ) OR ¹⁰ , -OC (O) R ⁹ , -C (O) N (R ¹⁰ ) ₂ , -OC (O) N (R ¹⁰ ) ₂ , -NR ¹⁰ C (O) N (R ¹⁰ ) ₂ , -NR ¹⁰ C (O) R ⁹ , -NR ¹⁰ C (O) OR ⁹ , C _1-6 alkyl, -C _1-6 alkyl-R ⁹ , -C _1-6 alkyl-OH, -C _1-6 Alkyl-OR ⁹ , -C _1-6 Alkyl-N (R ¹⁰ ) ₂ , -C _1-6 Alkyl-C (O) OR ¹⁰ , C _2-6 Alkenyl, -C _2-6 Alkenyl-C (O) OR ¹⁰ , C _2-6 alkynyl, C _1-6 haloalkyl, C _1-6 haloalkyl-OH, C _3-8 cycloalkyl, -C _1-6 alkyl-C _3-8 cycloalkyl, phenyl, -C _1- Selected from ₆ Alkyl-Phenyl, C _2-9 Heterocycloalkyl, and C _1-9 Heteroaryl; where phenyl, -C _1-6 Alkyl-Phenyl, and C _1-9 Heteroaryl are halogens, C. Arbitrarily substituted with one, two, or three groups independently selected from _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, and C _2-9 heterocycloalkyl; and Here, the C _2-9 heterocycloalkyl is optionally substituted with one, two, or three groups independently selected from halogen, C _1-6 alkyl, C _1-6 haloalkyl, and oxo. ,
R ⁶ is -C (O) OR ⁷ , -C (O) NHS (O) ₂ N (R ¹⁰ ) ₂ ,

And
R ⁷ is independently selected from H and C _1-6 alkyl, respectively.
R ⁸ are independently halogen, -OH, -OR ⁹ , -N (R ¹⁰ ) ₂ , -S (O) R ⁹ , -S (O) ₂ R ⁹ , -NHS (O) ₂ R ⁹ , -S (O) ₂ N (R ¹⁰ ) ₂ , -C (O) NHS (O) ₂ N (R ¹⁰ ) ₂ , -C (O) R ⁹ , -C (O) OR ¹⁰ , -OC ( O) R ⁹ , -C (O) N (R ¹⁰ ) ₂ , -OC (O) N (R ¹⁰ ) ₂ , -NR ¹⁰ C (O) N (R ¹⁰ ) ₂ , -NR ¹⁰ C (O) R ⁹ , -NR ¹⁰ C (O) OR ⁹ , C _1-6 alkyl, -C _1-6 alkyl-OH, -C _1-6 alkyl-OR ⁹ , -C _1-6 alkyl-N (R ¹⁰ ) ₂ , -C _1-6 alkyl-C (O) OR ¹⁰ , C _1-6 haloalkyl, C _1-6 haloalkyl-OH, C _3-8 cycloalkyl, -C _1-6 alkyl-C _3-8 cycloalkyl , Phenyl, -C _1-6 alkyl-phenyl, C _2-9 heterocycloalkyl, and C _1-9 heteroaryl; where phenyl, -C _1-6 alkyl-phenyl, and C _1-9 Heteroaryl is one, two or three groups independently selected from halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, and C _2-9 heterocycloalkyl. And where the C _2-9 heterocycloalkyl is selected independently of halogen, C _1-6 alkyl, C _1-6 haloalkyl, and oxo, one, two, or three. Arbitrarily replaced by one group,
R ⁹ are independently C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, -C _1-6 alkyl-C _3-8 cycloalkyl, phenyl, -C _1-6 alkyl- Selected from phenyl, C _2-9 heterocycloalkyl, -C _1-6 alkyl-C _2-9 heterocycloalkyl, C _2-9 heteroaryl, and -C _1-6 alkyl-C _2-9 heteroaryl, Here, C _1-6 alkyl, phenyl, -C _1-6 alkyl-phenyl, -C _1-6 alkyl-C _2-9 heterocycloalkyl, C _2-9 heteroaryl, and -C _1-6 alkyl- C _2-9 heteroaryls are C _1-6 alkyl, -OR ¹¹ , -N (R ¹¹ ) ₂ , C _1-6 alkyl, C _3-8 cycloalkyl, -N (R ¹¹ ) C (O) R. It is optionally substituted with one or two groups independently selected from ¹² , -C (O) R ¹² , and -C (O) OR ¹² .
R ¹⁰ are independently H, C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, -C _1-6 alkyl-C _3-8 cycloalkyl, phenyl, -C _1-6 . Selected from alkyl-phenyl and C _2-9 heteroaryl, where C _1-6 alkyl, phenyl, -C _1-6 alkyl-phenyl, and C _2-9 heteroaryl are halogen, C _1-6 . It is optionally substituted with one or two groups independently selected from alkyl, -N (R ¹¹ ) ₂ , and -C (O) OR ¹² ; or two R ^10s , and they are combined. The nitrogen atoms present together are 5-membered or optionally substituted with one, two, or three groups independently selected from C _1-6 alkyl, oxo, and -C (O) OH. Forming a 6-membered heterocycloalkyl ring,
R ¹¹ is independently selected from H and C _1-6 alkyl, respectively.
^R12 is independently selected from H and C _1-6 alkyl
n is 0, 1, 2, or 3
p is 0, 1, 2, 3, 4, or 5 and
q is 0, 1, 2, 3, or 4,
A compound, or a pharmaceutically acceptable salt or solvate thereof. A compound having the structure of formula (I), or a pharmaceutically acceptable salt or solvate thereof.

During the ceremony
R ¹ is -CH ₂ R ⁴ , -CN, -B (OH) ₂ , -N (R ¹⁰ ) ₂ , -NR ¹⁰ C (O) R ⁹ , -C (O) OH, -CH ₂ C ( O) OH, -C (O) N (R ¹⁰ ) ₂ , -C (O) NHS (O) ₂ N (R ¹⁰ ) ₂ , -C _1-6 alkyl-OH, C _3-8 cycloalkyl,

Alternatively, it is a 5- or ⁶ -membered heteroaryl optionally substituted with one, two, or three R8 groups.
R ² is H, -OH, -N (R ¹⁰ ) ₂ , -NHS (O) ₂ R ⁹ , -S (O) ₂ N (R ¹⁰ ) ₂ , -C (O) N (R ¹⁰ ) ₂ , -OC (O) N (R ¹⁰ ) ₂ , -OC _1-6 alkyl, -C _1-6 alkyl-OH, -C _1-6 alkyl-OR ⁹ , -C _1-6 alkyl-N ( R ¹⁰ ) ₂ , C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _3-8 cycloalkyl.
R ³ are independently halogen, -CN, -OH, -OR ⁹ , -SR ⁹ , -N (R ¹⁰ ) ₂ , -S (O) R ⁹ , -S (O) ₂ R ⁹ ,- NHS (O) ₂ R ⁹ , -S (O) ₂ N (R ¹⁰ ) ₂ , -C (O) R ⁹ , -C (O) OR ¹⁰ , -OC (O) R ⁹ , -C (O) N (R ¹⁰ ) ₂ , -OC (O) N (R ¹⁰ ) ₂ , -NR ¹⁰ C (O) N (R ¹⁰ ) ₂ , -NR ¹⁰ C (O) R ⁹ , -NR ¹⁰ C (O) OR ⁹ , C _1-6 alkyl, -C _1-6 alkyl-OH, -C _1-6 alkyl-OR ⁹ , -C _1-6 alkyl-N (R ¹⁰ ) ₂ , C _2-6 alkenyl, C ₂ Selected from _-6 alkynyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, and -C _1-6 alkyl-C _3-8 cycloalkyl.
^R4 is

And;
R ⁵ are independently halogen, -CN, -OH, -OR ⁹ , -SR ⁹ , -N (R ¹⁰ ) ₂ , -S (O) R ⁹ , -S (O) ₂ R ⁹ ,- NHS (O) ₂ R ⁹ , -S (O) ₂ N (R ¹⁰ ) ₂ , -C (O) NHS (O) ₂ N (R ¹⁰ ) ₂ , -C (O) R ⁹ , -C (O) ) OR ¹⁰ , -OC (O) R ⁹ , -C (O) N (R ¹⁰ ) ₂ , -OC (O) N (R ¹⁰ ) ₂ , -NR ¹⁰ C (O) N (R ¹⁰ ) ₂ , -NR ¹⁰ C (O) R ⁹ , -NR ¹⁰ C (O) OR ⁹ , C _1-6 alkyl, -C _1-6 alkyl-OH, -C _1-6 alkyl-OR ⁹ , -C _1-6 Alkyl-N (R ¹⁰ ) ₂ , -C _1-6 alkyl-C (O) OR ¹⁰ , C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _1-6 haloalkyl-OH, C Selected from _3-8 cycloalkyl, -C _1-6 alkyl-C _3-8 cycloalkyl, phenyl, -C _1-6 alkyl-phenyl, C _2-9 heterocycloalkyl, and C _1-9 heteroaryl; Here, phenyl, -C _1-6 alkyl-phenyl, and C _1-9 heteroaryl are halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, and C _2-9 hetero. It is optionally substituted with one, two, or three groups independently selected from cycloalkyl; and where C _2-9 heterocycloalkyl is halogen, C _1-6 alkyl, C _1-6 . Arbitrarily substituted with one, two, or three groups independently selected from haloalkyl, and oxo,
R ⁶ is -C (O) OR ⁷ , -C (O) NHS (O) ₂ N (R ¹⁰ ) ₂ ,

And
R ⁷ is independently selected from H and C _1-6 alkyl, respectively.
R ⁸ are independently halogen, -OH, -OR ⁹ , -N (R ¹⁰ ) ₂ , -S (O) R ⁹ , -S (O) ₂ R ⁹ , -NHS (O) ₂ R ⁹ , -S (O) ₂ N (R ¹⁰ ) ₂ , -C (O) NHS (O) ₂ N (R ¹⁰ ) ₂ , -C (O) R ⁹ , -C (O) OR ¹⁰ , -OC ( O) R ⁹ , -C (O) N (R ¹⁰ ) ₂ , -OC (O) N (R ¹⁰ ) ₂ , -NR ¹⁰ C (O) N (R ¹⁰ ) ₂ , -NR ¹⁰ C (O) R ⁹ , -NR ¹⁰ C (O) OR ⁹ , C _1-6 alkyl, -C _1-6 alkyl-OH, -C _1-6 alkyl-OR ⁹ , -C _1-6 alkyl-N (R ¹⁰ ) ₂ , -C _1-6 alkyl-C (O) OR ¹⁰ , C _1-6 haloalkyl, C _1-6 haloalkyl-OH, C _3-8 cycloalkyl, -C _1-6 alkyl-C _3-8 cycloalkyl , Phenyl, -C _1-6 alkyl-phenyl, C _2-9 heterocycloalkyl, and C _1-9 heteroaryl; where phenyl, -C _1-6 alkyl-phenyl, and C _1-9 Heteroaryl is one, two or three groups independently selected from halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, and C _2-9 heterocycloalkyl. And where the C _2-9 heterocycloalkyl is selected independently of halogen, C _1-6 alkyl, C _1-6 haloalkyl, and oxo, one, two, or three. Arbitrarily replaced by one group,
R ⁹ are independently C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, -C _1-6 alkyl-C _3-8 cycloalkyl, phenyl, -C _1-6 alkyl- Selected from phenyl, C _2-9 heterocycloalkyl, -C _1-6 alkyl-C _2-9 heterocycloalkyl, C _2-9 heteroaryl, and -C _1-6 alkyl-C _2-9 heteroaryl, Here, C _1-6 alkyl, phenyl, -C _1-6 alkyl-phenyl, -C _1-6 alkyl-C _2-9 heterocycloalkyl, C _2-9 heteroaryl, and -C _1-6 alkyl- C _2-9 heteroaryls are C _1-6 alkyl, -OR ¹¹ , -N (R ¹¹ ) ₂ , C _1-6 alkyl, C _3-8 cycloalkyl, -C (O) R ¹² , and -C. (O) Arbitrarily substituted with one or two groups independently selected from OR ¹²
R ¹⁰ are independently H, C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, -C _1-6 alkyl-C _3-8 cycloalkyl, phenyl, -C _1-6 . Selected from alkyl-phenyl and C _2-9 heteroaryl, where C _1-6 alkyl, phenyl, -C _1-6 alkyl-phenyl, and C _2-9 heteroaryl are halogen, C _1-6 . It is optionally substituted with one or two groups independently selected from alkyl, -N (R ¹¹ ) ₂ , and -C (O) OR ¹² ; or two R ^10s , and they are combined. The nitrogen atoms present together are 5-membered or optionally substituted with one, two, or three groups independently selected from C _1-6 alkyl, oxo, and -C (O) OH. Forming a 6-membered heterocycloalkyl ring,
R ¹¹ is independently selected from H and C _1-6 alkyl, respectively.
^R12 is independently selected from H and C _1-6 alkyl
n is 0, 1, 2, or 3
p is 0, 1, 2, 3, 4, or 5 and
q is 0, 1, 2, 3, or 4,
A compound, or a pharmaceutically acceptable salt or solvate thereof. R ¹ is

The compound according to any one of claims 1-3, or a pharmaceutically acceptable salt or solvate thereof. The compound according to any one of claims 1-4, wherein p is 0, 1, or 2, or a pharmaceutically acceptable salt or solvate thereof. R ⁵ are independently halogen, -OH, -OR ⁹ , -N (R ¹⁰ ) ₂ , -S (O) ₂ R ⁹ , -NHS (O) ₂ R ⁹ , -S (O) ₂ N. (R ¹⁰ ) ₂ , -C (O) NHS (O) ₂ N (R ¹⁰ ) ₂ , -C (O) R ⁹ , -C (O) OR ¹⁰ , -OC (O) R ⁹ , -C ( O) N (R ¹⁰ ) ₂ , -OC (O) N (R ¹⁰ ) ₂ , -NR ¹⁰ C (O) N (R ¹⁰ ) ₂ , -NR ¹⁰ C (O) R ⁹ , C _1-6 alkyl , -C _1-6 alkyl-OH, -C _1-6 alkyl-OR ⁹ , -C _1-6 alkyl-N (R ¹⁰ ) ₂ , -C _1-6 alkyl-C (O) OR ¹⁰ , C ₁ One of claims 1-5, selected from _-6 haloalkyl, C _1-6 haloalkyl-OH, C _3-8 cycloalkyl, C _2-9 heterocycloalkyl, and C _1-9 heteroaryl. The compound described, or a pharmaceutically acceptable salt or admixture thereof. R ⁵ are independently halogen, -OH, -OR ⁹ , -N (R ¹⁰ ) ₂ , -C (O) NHS (O) ₂ N (R ¹⁰ ) ₂ , -C (O) OR ¹⁰ , From -C (O) N (R ¹⁰ ) ₂ , -NR ¹⁰ C (O) R ⁹ , C _1-6 alkyl, -C _1-6 alkyl-C (O) OR ¹⁰ , and C _1-9 heteroaryl The compound according to any one of claims 1-6, or a pharmaceutically acceptable salt or solvate thereof, which is selected. R ⁵ are independently -OR ⁹ , -C (O) OR ¹⁰ , -C (O) N (R ¹⁰ ) ₂ , C _1-6 alkyl, -C _1-6 alkyl-C (O) OR. ¹⁰ and

The compound according to any one of claims 1-7, or a pharmaceutically acceptable salt or solvate thereof, which is selected from the above. R ⁵ is the compound according to any one of claims 1-8, or a pharmaceutically acceptable salt or solvate thereof, independently selected from −C (O) OR ¹⁰ . The compound according to any one of claims 1-7, wherein R ⁵ is independently selected from -OH, -OR ⁹ and -C _1-6 alkyl-C (O) OR ¹⁰ . The pharmaceutically acceptable salt or solvate. R ⁹ is the compound of claim 10, or a pharmaceutically acceptable salt or solvate thereof, which is a C _1-6 alkyl optionally substituted with —C (O) OR ¹² . R ¹⁰ is the compound according to any one of claims 1-11, or a pharmaceutically acceptable salt or solvate thereof, independently selected from H and C _1-6 alkyl, respectively. The compound according to any one of claims 1-12, or a pharmaceutically acceptable salt or solvate thereof, wherein p is 1 or 2. The compound according to any one of claims 1-13, or a pharmaceutically acceptable salt or solvate thereof, wherein p is 1. p is 2, the compound according to any one of claims 1-13, or a pharmaceutically acceptable salt or solvate thereof. The compound according to any one of claims 1-5, or a pharmaceutically acceptable salt or solvate thereof, wherein p is 0. The compound according to any one of claims 1-3, wherein ^R1 is a 5- or ⁶ -membered heteroaryl optionally substituted with one, two, or three R8 groups, or a compound thereof. A pharmaceutically acceptable salt or solvate. The compound of claim 17, or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is a 5-membered heteroaryl optionally substituted with one, two, or three R ⁸ groups. thing. R ¹ is a 5-membered heteroaryl optionally substituted with 1, ² , or 3 R8 groups, wherein the 5-membered heteroaryl is oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, The compound according to claim 17 or 18, or a pharmaceutically acceptable salt or solvate thereof, selected from pyrrolyl, imidazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, and thiadiazolyl. R ¹ is a 5-membered heteroaryl optionally substituted with one or two R8 groups, wherein the ⁵ -membered heteroaryl is oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, tetrazolyl, And isoxazolyl, the compound according to any one of claims 17-19, or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 17, or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is a 6-membered heteroaryl optionally substituted with 1, 2, or 3 R ⁸ groups. thing. R ¹ is a 6-membered heteroaryl optionally substituted with 1, ² , or 3 R8 groups, wherein the 6-membered heteroaryl is pyridinyl, pyrimidinyl, pyrazinyl, pyridadinyl, and triazineyl. The compound according to claim 21, or a pharmaceutically acceptable salt or solvate thereof, which is selected from the above. ^R1 is a 6-membered heteroaryl optionally substituted with 1 or ² R8 groups, wherein the 6-membered heteroaryl is selected from pyridinyl and pyrimidinyl, claim 21 or 22. The compound described, or a pharmaceutically acceptable salt or solvate thereof. Any of claims 17-23, each of which is independently selected from halogen, —C ⁽ O) OR ¹⁰ , C _1-6 alkyl, and —C _1-6 alkyl—C (O) OR ¹⁰ . The compound according to one, or a pharmaceutically acceptable salt or solvate thereof. R ⁸ is the compound according to any one of claims 17-24, or a pharmaceutically acceptable salt or solvate thereof, independently selected from —C (O) OR ¹⁰ . The compound according to any one of claims 17-19, wherein R ¹ is an unsubstituted 5-membered heteroaryl selected from oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, tetrazolyl, and isoxazolyl. Or its pharmaceutically acceptable salt or solvate. ^R1 is the compound according to any one of claims 21-23, which is an unsubstituted 6-membered heteroaryl selected from pyridinyl and pyrimidinyl, or a pharmaceutically acceptable salt or solvate thereof. .. The compound according to any one of claims 1-3, wherein R ¹ is −C (O) N (R ¹⁰ ) ₂ , or a pharmaceutically acceptable salt or solvate thereof. R ¹ is −N (R ¹⁰ ) ₂ , the compound according to any one of claims 1-3, or a pharmaceutically acceptable salt or solvate thereof. R ¹⁰ are independently H, C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, -C _1-6 alkyl-C _3-8 cycloalkyl, phenyl, -C _1-6 . Selected from alkyl-phenyl and C _2-9 heteroaryl, where C _1-6 alkyl, phenyl, -C _1-6 alkyl-phenyl, and C _2-9 heteroaryl are halogen, C _1-6 . The compound according to claim 28 or 29, which is optionally substituted with one or two groups independently selected from alkyl, -N (R ¹¹ ) ₂ , and -C (O) OR ¹² . A pharmaceutically acceptable salt or solvate. R ¹⁰ is independently selected from H, C _1-6 alkyl, C _3-8 cycloalkyl, phenyl, and C _2-9 heteroaryl, where C _1-6 alkyl, phenyl, and C ₂ are selected. _-9 heteroaryl is optionally substituted with one or two groups independently selected from halogen, C _1-6 alkyl, -N (R ¹¹ ) ₂ , and -C (O) OR ¹² . The compound according to any one of claims 28-30, or a pharmaceutically acceptable salt or solvate thereof. The compound according to any one of claims 28-31, wherein R ¹⁰ is independently selected from H and C _1-6 alkyl optionally substituted with —C (O) OR ¹² . The pharmaceutically acceptable salt or solvate. The two ^R10s , and the nitrogen atom to which they are attached, together are one, two, or three groups independently selected from C _1-6 alkyl, oxo, and -C (O) OH. The compound according to claim 28 or 29, or a pharmaceutically acceptable salt or solvate thereof, which forms a 5- or 6-membered heterocycloalkyl ring optionally substituted with. The compound according to claim 33, or a pharmaceutical agent thereof, wherein the two ^R10s and the nitrogen atom to which they are bonded together form a 5-membered heterocycloalkyl ring substituted with —C (O) OH. Acceptable salt or solvate. The compound according to claim 33, or a pharmaceutical agent thereof, wherein the two ^R10s and the nitrogen atom to which they are bonded together form a 6-membered heterocycloalkyl ring substituted with —C (O) OH. Acceptable salt or solvate. The compound according to any one of claims 1-3, wherein R ¹ is —C (O) OH, or a pharmaceutically acceptable salt or solvate thereof. R ¹ is

The compound according to any one of claims 1-3, or a pharmaceutically acceptable salt or solvate thereof. The compound according to any one of claims 1-37, wherein R ² is H, -OH, -N (R ¹⁰ ) ₂ , or -OC _1-6 alkyl, or pharmaceutically acceptable thereof. Possible salt or solvate. The compound according to any one of claims 1-38, or a pharmaceutically acceptable salt or solvate thereof, wherein R ² is —OC _1-6 alkyl. R ² is —OCH ₂ CH ₃ , the compound according to any one of claims 1-39, or a pharmaceutically acceptable salt or solvate thereof. ^R2 is H, the compound according to any one of claims 1-38, or a pharmaceutically acceptable salt or solvate thereof. n is 1, the compound according to any one of claims 1-41, or a pharmaceutically acceptable salt or solvate thereof. R ³ are independently halogen, -OH, -OR ⁹ , -N (R ¹⁰ ) ₂ , C _1-6 alkyl, -C _1-6 alkyl-OH, -C _1-6 alkyl-OR ⁹ , respectively. And C _1-6 haloalkyl, the compound according to any one of claims 1-42, or a pharmaceutically acceptable salt or solvate thereof. The compound according to any one of claims 1-43 ^, or a pharmaceutically acceptable salt thereof, each of which is independently selected from halogen, -OR ⁹ , and C _1-6 alkyl. Solvated product. The compound according to any one of claims 1-44, wherein R ³ is −OR ⁹ and R ⁹ is C _3-8 cycloalkyl, respectively, or a pharmaceutically acceptable salt or solvate thereof. .. The compound according to any one of claims 1-41, wherein n is 0, or a pharmaceutically acceptable salt or solvate thereof.

A compound selected from, or a pharmaceutically acceptable salt or solvate thereof.

A compound selected from, or a pharmaceutically acceptable salt or solvate thereof.

A compound selected from, or a pharmaceutically acceptable salt or solvate thereof.

A compound selected from, or a pharmaceutically acceptable salt or solvate thereof. A pharmaceutical composition comprising the compound according to any one of claims 1-50, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient. A method of treating an inflammatory bowel disease in a patient, wherein the method is a therapeutically effective amount of the compound according to any one of claims 1-50, or a pharmaceutically acceptable salt or solvent thereof. A method comprising the step of administering a Japanese product to the patient. 52. The method of claim 52, wherein the inflammatory bowel disease is selected from Crohn's disease, ulcerative colitis, and perianal Crohn's disease. A method of regulating GPR35 activity, wherein the GPR35 or a portion thereof is combined with the compound according to any one of claims 1-50, or a pharmaceutically acceptable salt or solvate thereof. A method comprising contacting.